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Ng B, Huang KY, Pua CJ, Viswanathan S, Lim WW, Kuthubudeen FF, Liu YN, Hii AA, George BL, Widjaja AA, Petretto E, Cook SA. Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration. Nat Commun 2024; 15:8530. [PMID: 39358385 PMCID: PMC11448503 DOI: 10.1038/s41467-024-52810-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
In lung disease, persistence of KRT8-expressing aberrant basaloid cells in the alveolar epithelium is associated with impaired tissue regeneration and pathological tissue remodeling. We analyzed single cell RNA sequencing datasets of human interstitial lung disease and found the profibrotic Interleukin-11 (IL11) cytokine to be highly and specifically expressed in aberrant KRT8+ basaloid cells. IL11 is similarly expressed by KRT8+ alveolar epithelial cells lining fibrotic lesions in a mouse model of interstitial lung disease. Stimulation of alveolar epithelial cells with IL11 causes epithelial-to-mesenchymal transition and promotes a KRT8-high state, which stalls the beneficial differentiation of alveolar type 2 (AT2)-to-AT1 cells. Inhibition of IL11-signaling in AT2 cells in vivo prevents the accumulation of KRT8+ cells, enhances AT1 cell differentiation and blocks fibrogenesis, which is replicated by anti-IL11 therapy. These data show that IL11 inhibits reparative AT2-to-AT1 differentiation in the damaged lung to limit endogenous alveolar regeneration, resulting in fibrotic lung disease.
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Affiliation(s)
- Benjamin Ng
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore.
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
| | - Kevin Y Huang
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Chee Jian Pua
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore
| | - Sivakumar Viswanathan
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Wei-Wen Lim
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Fathima F Kuthubudeen
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Yu-Ning Liu
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - An An Hii
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore
| | - Benjamin L George
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Anissa A Widjaja
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Enrico Petretto
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
- Center for Computational Biology, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Stuart A Cook
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore.
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
- MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, United Kingdom.
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Zhu H, Zhang R, Bao T, Ma M, Li J, Cao L, Yu B, Hu J, Tian Z. Interleukin-11 Is Involved in Hyperoxia-induced Bronchopulmonary Dysplasia in Newborn Mice by Mediating Epithelium-Fibroblast Cross-talk. Inflammation 2024:10.1007/s10753-024-02089-0. [PMID: 39046604 DOI: 10.1007/s10753-024-02089-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 06/22/2024] [Accepted: 06/24/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND Bronchopulmonary dysplasia (BPD) is a chronic lung disorder predominantly affecting preterm infants. Oxygen therapy, a common treatment for BPD, often leads to hyperoxia-induced pulmonary damage, particularly targeting alveolar epithelial cells (AECs). Crucially, disrupted lung epithelium-fibroblast interactions significantly contribute to BPD's pathogenesis. Previous studies on interleukin-11 (IL-11) in lung diseases have yielded conflicting results. Recent research, however, highlights IL-11 as a key regulator of fibrosis, stromal inflammation, and epithelial dysfunction. Despite this, the specific role of IL-11 in BPD remains underexplored. Our transcriptome analysis of normal and hyperoxia-exposed murine lung tissues revealed an increased expression of IL-11 RNA. This study aimed to investigate IL-11's role in modulating the disrupted interactions between AECs and fibroblasts in BPD. METHODS BPD was modeled in vivo by exposing C57BL/6J neonatal mice to hyperoxia. Histopathological changes in lung tissue were evaluated with hematoxylin-eosin staining, while lung fibrosis was assessed using Masson staining and immunohistochemistry (IHC). To investigate IL-11's role in pulmonary injury contributing to BPD, IL-11 levels were reduced through intraperitoneal administration of IL-11RαFc in hyperoxia-exposed mice. Additionally, MLE-12 cells subjected to 95% oxygen were collected and co-cultured with mouse pulmonary fibroblasts (MPFs) to measure α-SMA and Collagen I expression levels. IL-11 levels in the supernatants were quantified using an enzyme-linked immunosorbent assay (ELISA). RESULTS Both IHC and Masson staining revealed that inhibiting IL-11 expression alleviated pulmonary fibrosis in neonatal mice induced by hyperoxia, along with reducing the expression of fibrosis markers α-SMA and collagen I in lung tissue. In vitro analysis showed a significant increase in IL-11 levels in the supernatant of MLE-12 cells treated with hyperoxia. Silencing IL-11 expression in MLE-12 cells reduced α-SMA and collagen I concentrations in MPFs co-cultured with the supernatant of hyperoxia-treated MLE-12 cells. Additionally, ERK inhibitors decreased α-SMA and collagen I levels in MPFs co-cultured with the supernatant of hyperoxia-treated MLE-12 cells. Clinical studies found increased IL-11 levels in tracheal aspirates (TA) of infants with BPD. CONCLUSION This research reveals that hyperoxia induces IL-11 secretion in lung epithelium. Additionally, IL-11 derived from lung epithelium emerged as a crucial mediator in myofibroblast differentiation via the ERK signaling pathway, highlighting its potential therapeutic value in BPD treatment.
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Affiliation(s)
- Haiyan Zhu
- Department of Pediatrics, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Rongrong Zhang
- Department of Pediatrics, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Tianping Bao
- Department of Neonatology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Mengmeng Ma
- Department of Neonatology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Jingyan Li
- Department of Neonatology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Linxia Cao
- Department of Neonatology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Bingrui Yu
- Department of Neonatology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Jian Hu
- Department of Pediatrics, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China.
| | - Zhaofang Tian
- Department of Neonatology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China.
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Cho WJ, Pulimamidi VK, Mittal SK, Chauhan SK. Mesenchymal stromal cells protect tissues from Th1 immune responses via IL-11 secretion. FASEB J 2024; 38:e23683. [PMID: 38758184 PMCID: PMC11149610 DOI: 10.1096/fj.202400078r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 04/05/2024] [Accepted: 05/07/2024] [Indexed: 05/18/2024]
Abstract
Mesenchymal stromal cells (MSCs) have been shown to modulate the function of various subsets of T cells such as naïve CD4+ T cells and IFNγ+CD4+ Th1 cells; however, mechanisms underlying this regulation have not been fully deciphered. Our in vitro culture assays demonstrate that MSCs suppress the activation and function of CD4+ T cells by secreting interleukin 11, and neutralization of IL11 abrogates MSC-mediated suppression of CD4+ T cell function. Moreover, delayed-type, exogenous supplementation of IL11 significantly suppressed IFNγ+ expression by Th1 cells. Th1 and CD8+ cells play central roles in T cell-mediated tissue damage. Using a murine model of hypersensitivity response to study T cell-mediated tissue damage, we show that silencing IL11 in MSCs significantly abates the capacity of MSCs to suppress the generation of IFNγ-secreting CD4+ and CD8+ cells, failing to prevent T cell-mediated tissue inflammation and tissue damage.
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Affiliation(s)
- WonKyung J. Cho
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, Massachusetts, 02114, USA
| | - Vinay K. Pulimamidi
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, Massachusetts, 02114, USA
| | - Sharad K. Mittal
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, Massachusetts, 02114, USA
| | - Sunil K. Chauhan
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, Massachusetts, 02114, USA
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Sang L, Gong X, Huang Y, Zhang L, Sun J. Immunotherapeutic implications on targeting the cytokines produced in rhinovirus-induced immunoreactions. FRONTIERS IN ALLERGY 2024; 5:1427762. [PMID: 38859875 PMCID: PMC11163110 DOI: 10.3389/falgy.2024.1427762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 05/13/2024] [Indexed: 06/12/2024] Open
Abstract
Rhinovirus is a widespread virus associated with several respiratory diseases, especially asthma exacerbation. Currently, there are no accurate therapies for rhinovirus. Encouragingly, it is found that during rhinovirus-induced immunoreactions the levels of certain cytokines in patients' serum will alter. These cytokines may have pivotal pro-inflammatory or anti-inflammatory effects via their specific mechanisms. Thus far, studies have shown that inhibitions of cytokines such as IL-1, IL-4, IL-5, IL-6, IL-13, IL-18, IL-25, and IL-33 may attenuate rhinovirus-induced immunoreactions, thereby relieving rhinovirus infection. Furthermore, such therapeutics for rhinovirus infection can be applied to viruses of other species, with certain practicability.
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Affiliation(s)
- Le Sang
- Department of Medicine, Shaoxing University, Shaoxing City, Zhejiang Province, China
| | - Xia Gong
- Department of Medicine, Shaoxing University, Shaoxing City, Zhejiang Province, China
| | - Yunlei Huang
- Department of Medicine, Shaoxing University, Shaoxing City, Zhejiang Province, China
| | - Linling Zhang
- Department of Respiratory Medicine, Shaoxing People’s Hospital, Shaoxing City, Zhejiang Province, China
| | - Jian Sun
- Department of Respiratory Medicine, Shaoxing People’s Hospital, Shaoxing City, Zhejiang Province, China
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Han Y, Gao H, Gan X, Liu J, Bao C, He C. Roles of IL-11 in the regulation of bone metabolism. Front Endocrinol (Lausanne) 2024; 14:1290130. [PMID: 38352248 PMCID: PMC10862480 DOI: 10.3389/fendo.2023.1290130] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 12/29/2023] [Indexed: 02/16/2024] Open
Abstract
Bone metabolism is the basis for maintaining the normal physiological state of bone, and imbalance of bone metabolism can lead to a series of metabolic bone diseases. As a member of the IL-6 family, IL-11 acts primarily through the classical signaling pathway IL-11/Receptors, IL-11 (IL-11R)/Glycoprotein 130 (gp130). The regulatory role of IL-11 in bone metabolism has been found earlier, but mainly focuses on the effects on osteogenesis and osteoclasis. In recent years, more studies have focused on IL-11's roles and related mechanisms in different bone metabolism activities. IL-11 regulates osteoblasts, osteoclasts, BM stromal cells, adipose tissue-derived mesenchymal stem cells, and chondrocytes. It's involved in bone homeostasis, including osteogenesis, osteolysis, bone marrow (BM) hematopoiesis, BM adipogenesis, and bone metastasis. This review exams IL-11's role in pathology and bone tissue, the cytokines and pathways that regulate IL-11 expression, and the feedback regulations of these pathways.
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Affiliation(s)
| | | | - Xinling Gan
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | | | | | - Chengqi He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Metcalfe RD, Hanssen E, Fung KY, Aizel K, Kosasih CC, Zlatic CO, Doughty L, Morton CJ, Leis AP, Parker MW, Gooley PR, Putoczki TL, Griffin MDW. Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant. Nat Commun 2023; 14:7543. [PMID: 37985757 PMCID: PMC10662374 DOI: 10.1038/s41467-023-42754-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 10/20/2023] [Indexed: 11/22/2023] Open
Abstract
Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
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Affiliation(s)
- Riley D Metcalfe
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702, USA
| | - Eric Hanssen
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Ian Holmes Imaging Centre, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Ka Yee Fung
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Kaheina Aizel
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Clara C Kosasih
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Courtney O Zlatic
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Larissa Doughty
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Craig J Morton
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- CSIRO Biomedical Manufacturing Program, Clayton, Victoria, 3168, Australia
| | - Andrew P Leis
- Ian Holmes Imaging Centre, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Michael W Parker
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
- St Vincent's Institute of Medical Research, Fitzroy, Victoria, 3065, Australia
| | - Paul R Gooley
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Tracy L Putoczki
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia.
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia.
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Ye W, Wang Q, Zhao L, Wang C, Zhang D, Zhou M, Chen F, Wang W, Zhu Z, Guo W, Liu Y, Zou H, Xue Y. Blockade of IL-11 Trans-Signaling or JAK2/STAT3 Signaling Ameliorates the Profibrotic Effect of IL-11. Immunol Invest 2023; 52:703-716. [PMID: 37401665 DOI: 10.1080/08820139.2023.2222746] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2023]
Abstract
OBJECTIVES Systemic sclerosis (SSc) is a rare rheumatic disease characterized by vascular damage, dysregulated immune response, and fibrosis. Interleukin-11 (IL-11) is upregulated in SSc. This study aimed to investigate the pathological and therapeutic role of the IL-11 trans-signaling pathway in SSc. METHODS Plasma IL-11 level was evaluated in 32 patients with SSc and 15 healthy controls, while the expression levels of ADAM10, ADAM17, IL-11, IL-11 Rα, or IL-11 co-stained with CD3 or CD163 in the skin of SSc patients and healthy controls were analyzed. Fibroblasts were treated with IL-11 and ionomycin to evaluate the profibrotic effect of IL-11 trans-signaling pathway. TJ301 (sgp130Fc) and WP1066 (a JAK2/STAT3 inhibitor) intervention groups were set up to investigate the antifibrotic effect of targeting IL-11. RESULTS Levels of plasma IL-11 were extremely low in most SSc patients and healthy controls. In contrast, levels of IL-11, IL-11 Rα, and ADAM10, but not ADAM17, were significantly elevated in the skin of SSc patients. Moreover, the numbers of IL-11+ CD3+ cells and IL-11+ CD163+ cells were increased in the skin of SSc patients. Besides, IL-11 and ADAM10 were also elevated in the skin and pulmonary of bleomycin-induced SSc mouse. Fibroblasts co-stimulated with IL-11 and ionomycin showed increased expression of COL3 and phosphorylation of STAT3, which could be inhibited by TJ301 or WP1066. TJ301 also ameliorated skin and lung fibrosis in BLM-induced SSc mouse. CONCLUSIONS IL-11 induces fibrosis in SSc by regulating the trans-signaling pathway. Blockage of sgp130Fc or inhibition of the JAK2/STAT3 pathway could ameliorate the profibrotic effect of IL-11.
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Affiliation(s)
- Wenjing Ye
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qian Wang
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Li Zhao
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Changcheng Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dandan Zhang
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Mengyu Zhou
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Fangfang Chen
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Weiguo Wang
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Zaihua Zhu
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenyu Guo
- Clinical Development, I-Mab Biopharma, Hangzhou, China
| | - Yun Liu
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hejian Zou
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yu Xue
- Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
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Striz I, Golebski K, Strizova Z, Loukides S, Bakakos P, Hanania N, Jesenak M, Diamant Z. New insights into the pathophysiology and therapeutic targets of asthma and comorbid chronic rhinosinusitis with or without nasal polyposis. Clin Sci (Lond) 2023; 137:727-753. [PMID: 37199256 PMCID: PMC10195992 DOI: 10.1042/cs20190281] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/22/2023] [Accepted: 04/28/2023] [Indexed: 05/19/2023]
Abstract
Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) or without (CRSsNP) are chronic respiratory diseases. These two disorders often co-exist based on common anatomical, immunological, histopathological, and pathophysiological basis. Usually, asthma with comorbid CRSwNP is driven by type 2 (T2) inflammation which predisposes to more severe, often intractable, disease. In the past two decades, innovative technologies and detection techniques in combination with newly introduced targeted therapies helped shape our understanding of the immunological pathways underlying inflammatory airway diseases and to further identify several distinct clinical and inflammatory subsets to enhance the development of more effective personalized treatments. Presently, a number of targeted biologics has shown clinical efficacy in patients with refractory T2 airway inflammation, including anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab)/anti-IL5R (benralizumab), anti-IL-4R-α (anti-IL-4/IL-13, dupilumab), and anti-TSLP (tezepelumab). In non-type-2 endotypes, no targeted biologics have consistently shown clinical efficacy so far. Presently, multiple therapeutical targets are being explored including cytokines, membrane molecules and intracellular signalling pathways to further expand current treatment options for severe asthma with and without comorbid CRSwNP. In this review, we discuss existing biologics, those under development and share some views on new horizons.
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Affiliation(s)
- Ilja Striz
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Institute of Immunology and Microbiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Subdivision of Allergology and Clinical Immunology, Institute for Postgraduate Education in Medicine, Prague, Czech Republic
| | - Kornel Golebski
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands
| | - Zuzana Strizova
- Institute of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Stelios Loukides
- Department of Respiratory Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Petros Bakakos
- First Respiratory Medicine Department, National and Kapodistrian University of Athens, Athens, Greece
| | - Nicola A. Hanania
- Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Milos Jesenak
- Department of Pulmonology and Phthisiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, University Hospital in Martin, Slovakia
- Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, University Hospital in Martin, Slovakia
- Department of Clinical Immunology and Allergology, University Hospital in Martin, Slovakia
| | - Zuzana Diamant
- Department of Microbiology Immunology and Transplantation, KU Leuven, Catholic University of Leuven, Belgium
- Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Skane University Hospital, Lund University, Lund, Sweden
- Department of Respiratory Medicine, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Kortekaas RK, Geillinger-Kästle KE, Borghuis T, Belharch K, Webster M, Timens W, Burgess JK, Gosens R. Interleukin-11 disrupts alveolar epithelial progenitor function. ERJ Open Res 2023; 9:00679-2022. [PMID: 37228276 PMCID: PMC10204861 DOI: 10.1183/23120541.00679-2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/08/2023] [Indexed: 05/27/2023] Open
Abstract
Background Interleukin-11 (IL-11) is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. In IPF there is disrupted alveolar structural architecture, yet the effect of IL-11 on the dysregulated alveolar repair remains to be elucidated. Methods We hypothesised that epithelial-fibroblast communication associated with lung repair is disrupted by IL-11. Thus, we studied whether IL-11 affects the repair responses of alveolar lung epithelium using mouse lung organoids and precision-cut lung slices (PCLS). Additionally, we assessed the anatomical distribution of IL-11 and IL-11 receptor (IL-11R) in human control and IPF lungs using immunohistochemistry. Results IL-11 protein was observed in airway epithelium, macrophages and in IPF lungs, also in areas of alveolar type 2 (AT2) cell hyperplasia. IL-11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid co-cultures of epithelial cells with lung fibroblasts, IL-11 decreased organoid number and reduced the fraction of Prosurfactant Protein C-expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS exposed to IL-11, ciliated cell markers were increased. The response of primary human fibroblasts to IL-11 on gene expression level was minimal, though bulk RNA-sequencing revealed IL-11 modulated various processes which are associated with IPF, including unfolded protein response, glycolysis and Notch signalling. Conclusions IL-11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. Evidence for a contribution of dysregulated fibroblast-epithelial communication to this process is limited.
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Affiliation(s)
- Rosa K. Kortekaas
- Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
| | - Kerstin E. Geillinger-Kästle
- Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Theo Borghuis
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
| | - Kaoutar Belharch
- Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
| | - Megan Webster
- Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Wim Timens
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
| | - Janette K. Burgess
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
- These authors contributed equally
| | - Reinoud Gosens
- Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
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10
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Ma J, Xie Y, Xu Y, Gu P, Zhang Y, Fan L, Zhou Y, Wang H, Zhou T, He J, Wang D, Chen W. Neutralization of interleukin-11 attenuates silica particles-induced pulmonary inflammation and fibrosis in vivo. J Environ Sci (China) 2023; 126:772-783. [PMID: 36503802 DOI: 10.1016/j.jes.2022.03.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/04/2022] [Accepted: 03/08/2022] [Indexed: 06/17/2023]
Abstract
Environmental exposure to crystalline silica particles can lead to silicosis, which is one of the most serious pulmonary interstitial fibrosis around the world. Unfortunately, the exact mechanism on silicosis is unclear, and the effective treatments are lacking to date. In this study, we aim to explore the molecular mechanism by which interleukin-11 (IL-11) affects silica particles-induced lung inflammation and fibrosis. We observed that IL-11 expressions in mouse lungs were significantly increased after silica exposure, and maintained at high levels across both inflammation and fibrosis phase. Immunofluorescent dual staining further revealed that the overexpression of IL-11 mainly located in mouse lung epithelial cells and fibroblasts. Using neutralizing anti-IL-11 antibody could effectively alleviate the overexpression of pro-inflammatory cytokines (i.e., interleukin-6 and tumor necrosis factor-α) and fibrotic proteins (i.e., collagen type I and matrix metalloproteinase-2) induced by silica particles. Most importantly, the expressions of IL-11 receptor subunit α (IL-11Rα), Glycoprotein 130 (GP130), and phosphorylated extracellular signal-regulated kinase (p-ERK) were significantly increased in response to silica, whereas blocking of IL-11 markedly reduced their levels. All findings suggested that the overexpression of IL-11 was involved in the pathological of silicosis, while neutralizing IL-11 antibody could effectively alleviate the silica-induced lung inflammation and fibrosis by inhibiting the IL-11Rα/GP130/ERK signaling pathway. IL-11 might be a promising therapeutic target for lung inflammation and fibrosis caused by silica particles exposure.
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Affiliation(s)
- Jixuan Ma
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yujia Xie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yiju Xu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Pei Gu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yingdie Zhang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lieyang Fan
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yun Zhou
- State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 511436, China
| | - Haijiao Wang
- National Center of Occupational Safety and Health, National Health Commission, Beijing 102300, China
| | - Ting Zhou
- Department of Occupational and Environmental Health, School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Jintong He
- Zhuhai Center for Chronic Disease Control, Zhuhai 519000, China
| | - Dongming Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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11
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Johnston RA, Atkins CL, Siddiqui SR, Jackson WT, Mitchell NC, Spencer CY, Pilkington AW, Kashon ML, Haque IU. Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone. Am J Physiol Regul Integr Comp Physiol 2022; 323:R921-R934. [PMID: 36283092 PMCID: PMC9722265 DOI: 10.1152/ajpregu.00213.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/24/2022] [Accepted: 10/24/2022] [Indexed: 11/22/2022]
Abstract
Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O3), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O3, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O3-exposed IL-11Rα1-deficient as compared with O3-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O3-exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O3 exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.
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Affiliation(s)
- Richard A Johnston
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
- Division of Critical Care Medicine, Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Constance L Atkins
- Division of Pulmonary Medicine, Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Saad R Siddiqui
- Division of Critical Care Medicine, Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - William T Jackson
- Division of Critical Care Medicine, Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Nicholas C Mitchell
- Division of Critical Care Medicine, Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Chantal Y Spencer
- Section of Pediatric Pulmonology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Albert W Pilkington
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
| | - Michael L Kashon
- Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
| | - Ikram U Haque
- Division of Critical Care Medicine, Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
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12
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Margelidon-Cozzolino V, Tsicopoulos A, Chenivesse C, de Nadai P. Role of Th17 Cytokines in Airway Remodeling in Asthma and Therapy Perspectives. FRONTIERS IN ALLERGY 2022; 3:806391. [PMID: 35386663 PMCID: PMC8974749 DOI: 10.3389/falgy.2022.806391] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/10/2022] [Indexed: 12/07/2022] Open
Abstract
Airway remodeling is a frequent pathological feature of severe asthma leading to permanent airway obstruction in up to 50% of cases and to respiratory disability. Although structural changes related to airway remodeling are well-characterized, immunological processes triggering and maintaining this phenomenon are still poorly understood. As a consequence, no biotherapy targeting cytokines are currently efficient to treat airway remodeling and only bronchial thermoplasty may have an effect on bronchial nerves and smooth muscles with uncertain clinical relevance. Th17 cytokines, including interleukin (IL)-17 and IL-22, play a role in neutrophilic inflammation in severe asthma and may be involved in airway remodeling. Indeed, IL-17 is increased in sputum from severe asthmatic patients, induces the expression of "profibrotic" cytokines by epithelial, endothelial cells and fibroblasts, and provokes human airway smooth muscle cell migration in in vitro studies. IL-22 is also increased in asthmatic samples, promotes myofibroblast differentiation, epithelial-mesenchymal transition and proliferation and migration of smooth muscle cells in vitro. Accordingly, we also found high levels of IL-17 and IL-22 in a mouse model of dog-allergen induced asthma characterized by a strong airway remodeling. Clinical trials found no effect of therapy targeting IL-17 in an unselected population of asthmatic patients but showed a potential benefit in a sub-population of patients exhibiting a high level of airway reversibility, suggesting a potential role on airway remodeling. Anti-IL-22 therapies have not been evaluated in asthma yet but were demonstrated efficient in severe atopic dermatitis including an effect on skin remodeling. In this review, we will address the role of Th17 cytokines in airway remodeling through data from in vitro, in vivo and translational studies, and examine the potential place of Th17-targeting therapies in the treatment of asthma with airway remodeling.
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Affiliation(s)
- Victor Margelidon-Cozzolino
- Univ. Lille, CNRS, INSERM, CHU de Lille, Institut Pasteur de Lille, Unité INSERM U1019-UMR9017-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France
| | - Anne Tsicopoulos
- Univ. Lille, CNRS, INSERM, CHU de Lille, Institut Pasteur de Lille, Unité INSERM U1019-UMR9017-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France
| | - Cécile Chenivesse
- Univ. Lille, CNRS, INSERM, CHU de Lille, Institut Pasteur de Lille, Unité INSERM U1019-UMR9017-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France
- CRISALIS (Clinical Research Initiative in Severe Asthma: a Lever for Innovation & Science), F-CRIN Network, INSERM US015, Toulouse, France
| | - Patricia de Nadai
- Univ. Lille, CNRS, INSERM, CHU de Lille, Institut Pasteur de Lille, Unité INSERM U1019-UMR9017-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France
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13
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Wu P, Lin B, Huang S, Meng J, Zhang F, Zhou M, Hei X, Ke Y, Yang H, Huang D. IL-11 Is Elevated and Drives the Profibrotic Phenotype Transition of Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy. Front Endocrinol (Lausanne) 2022; 13:846106. [PMID: 35273577 PMCID: PMC8902078 DOI: 10.3389/fendo.2022.846106] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 01/24/2022] [Indexed: 12/30/2022] Open
Abstract
Orbital fibrosis is a hallmark of tissue remodeling in thyroid-associated ophthalmopathy (TAO). Previous studies have shown that interleukin (IL)-11 plays a pivotal profibrotic role in various inflammatory and autoimmune diseases. However, the expression pattern of IL-11 in patients with TAO and whether IL-11 is mechanistically linked with pathological fibrosis remains unknown. In this study, we investigated IL-11 levels in the serum and orbital connective tissue of patients with TAO, and evaluated the correlation of these levels with the patient's clinical activity score. We also evaluated the expression pattern of IL-11Rα in orbital connective tissue. Furthermore, we elucidated the regulatory factors, profibrotic function, and downstream signaling pathways for IL-11 in TAO using in vitro studies. IL-11 levels in serum and orbital connective tissues were increased in patients with TAO, as compared with healthy controls. In addition, both levels were positively correlated with disease activity. Single-cell RNA sequencing of orbital connective tissue indicated that IL-11Rα was dominantly expressed in orbital fibroblasts (OFs). RNA sequencing of paired unstimulated and transforming growth factor (TGF)-β1-stimulated samples demonstrated that upregulation of IL-11 expression defined the dominant transcriptional response. IL-11 signaling was also confirmed to be downstream of TGF-β1 and IL-1β. Therefore, we deduced that IL-11 protein is secreted in an autocrine loop in TAO. We also indicated that IL-11 mediated the profibrotic phenotype switch by inducing the expression of myofibroblast differentiation markers, including α-smooth muscle actin and collagen type I α1, which could be abrogated by an anti-IL-11 neutralizing antibody. Furthermore, we revealed that extracellular regulated protein kinase may be a crucial factor in the pro-fibrotic, translationally specific signaling activity of IL-11. These data demonstrate that IL-11 plays a crucial role in orbital fibroblast phenotype switching and may be a potential therapeutic target candidate for the treatment of TAO.
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Affiliation(s)
- Pengsen Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Bingying Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Siyu Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Jie Meng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Fan Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Min Zhou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Xiangqing Hei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Yu Ke
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Huasheng Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Danping Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
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14
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Alabed M, Elemam NM, Ramakrishnan RK, Sharif-Askari NS, Kashour T, Hamid Q, Halwani R. Therapeutic effect of statins on airway remodeling during asthma. Expert Rev Respir Med 2021; 16:17-24. [PMID: 34663161 DOI: 10.1080/17476348.2021.1987890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Asthma is a chronic inflammatory disease of the airways, which is usually characterized by remodeling, hyperresponsiveness and episodic obstruction of the airways. The underlying chronic airway inflammation leads to pathological restructuring of both the large and small airways. Since the effects of current asthma medications on airway remodeling have been met with contradictions, many therapeutic agents have been redirected from their primary use for the treatment of asthma. Such treatments, which could target several signaling molecules implicated in the inflammatory and airway remodeling processes of asthma, would be an ideal choice. AREAS COVERED Statins are effective serum cholesterol-lowering agents that were found to have potential anti-inflammatory and anti-remodeling properties. Literature search was done for the past 10 years to include research and review articles in the field of statins and asthma complications. In this review, we discuss the role of statins in airway tissue remodeling and their potential therapeutic modalities in asthma. EXPERT OPINION With improved understanding of the role of statins in airway remodeling and inflammation, statins represent a potential therapeutic option for various asthma phenotypes. Further research is warranted to optimize statins for asthma therapy through inhalation as a possible route of administration.
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Affiliation(s)
- Mashael Alabed
- Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Noha Mousaad Elemam
- Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Rakhee K Ramakrishnan
- Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Narjes Saheb Sharif-Askari
- Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Tarek Kashour
- Department of Cardiology, King Fahad Cardiac Center, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Qutayba Hamid
- Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Meakins-Christie Laboratories, Research Institute of the McGill University Healthy Center, McGill University, Montreal, Quebec, Canada.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Rabih Halwani
- Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
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15
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Fung KY, Louis C, Metcalfe RD, Kosasih CC, Wicks IP, Griffin MDW, Putoczki TL. Emerging roles for IL-11 in inflammatory diseases. Cytokine 2021; 149:155750. [PMID: 34689057 DOI: 10.1016/j.cyto.2021.155750] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/16/2022]
Abstract
Interleukin-11 (IL-11) is a cytokine that has been strongly implicated in the pathogenesis of fibrotic diseases and solid malignancies. Elevated IL-11 expression is also associated with several non-malignant inflammatory diseases where its function remains less well-characterized. Here, we summarize current literature surrounding the contribution of IL-11 to the pathogenesis of autoimmune inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, diabetes and systemic sclerosis, as well as other chronic inflammatory conditions such as periodontitis, asthma, chronic obstructive pulmonary disease, psoriasis and colitis.
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Affiliation(s)
- Ka Yee Fung
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3053, Australia.
| | - Cynthia Louis
- Department of Medical Biology, University of Melbourne, Victoria 3053, Australia; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia
| | - Riley D Metcalfe
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Technology Institute, University of Melbourne, Victoria 3010, Australia
| | - Clara C Kosasih
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Technology Institute, University of Melbourne, Victoria 3010, Australia
| | - Ian P Wicks
- Department of Medical Biology, University of Melbourne, Victoria 3053, Australia; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Rheumatology Unit, The Royal Melbourne Hospital, Victoria 3050, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Technology Institute, University of Melbourne, Victoria 3010, Australia
| | - Tracy L Putoczki
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3053, Australia.
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16
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Valentino SA, Chézeau L, Seidel C, Sébillaud S, Lorcin M, Chalansonnet M, Cosnier F, Gaté L. Exposure to TiO 2 Nanostructured Aerosol Induces Specific Gene Expression Profile Modifications in the Lungs of Young and Elderly Rats. NANOMATERIALS 2021; 11:nano11061466. [PMID: 34206090 PMCID: PMC8230065 DOI: 10.3390/nano11061466] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 12/24/2022]
Abstract
Although aging is associated with a higher risk of developing respiratory pathologies, very few studies have assessed the impact of age on the adverse effects of inhaled nanoparticles. Using conventional and transcriptomic approaches, this study aimed to compare in young (12–13-week-old) and elderly (19-month-old) fisher F344 rats the pulmonary toxicity of an inhaled nanostructured aerosol of titanium dioxide (TiO2). Animals were nose-only exposed to this aerosol at a concentration of 10 mg/m3 for 6 h per day, 5 days per week for 4 weeks. Tissues were collected immediately (D0), and 28 days after exposure (D28). A pulmonary influx of neutrophilic granulocytes was observed in exposed rats at D0, but diminished with time while remaining significant until D28. Similarly, an increased expression of several genes involved in inflammation at the two post-exposure time-points was seen. Apart from an age-specific pulmonary influx of lymphocyte, only slight differences in physio-pathological responses following TiO2 exposure between young and elderly animals were noticed. Conversely, marked age-related differences in gene expression profiles were observed making possible to establish lists of genes specific to each age group and post-exposure times. These results highlight different signaling pathways that were disrupted in rats according to their age.
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17
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Kortekaas RK, Burgess JK, van Orsoy R, Lamb D, Webster M, Gosens R. Therapeutic Targeting of IL-11 for Chronic Lung Disease. Trends Pharmacol Sci 2021; 42:354-366. [PMID: 33612289 DOI: 10.1016/j.tips.2021.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/11/2021] [Accepted: 01/25/2021] [Indexed: 02/07/2023]
Abstract
Interleukin (IL)-11 was originally recognized as an immunomodulatory and hematopoiesis-inducing cytokine. However, although IL-11 is typically not found in healthy individuals, it is now becoming evident that IL-11 may play a role in diverse pulmonary conditions, including IPF, asthma, and lung cancer. Additionally, experimental strategies targeting IL-11, such as humanized antibodies, have recently been developed, revealing the therapeutic potential of IL-11. Thus, further insight into the underlying mechanisms of IL-11 in lung disease may lead to the ability to interfere with pathological conditions that have a clear need for disease-modifying treatments, such as IPF. In this review, we outline the effects, expression, signaling, and crosstalk of IL-11 and focus on its role in lung disease and its potential as a therapeutic target.
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Affiliation(s)
- Rosa K Kortekaas
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Janette K Burgess
- Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Medical Biology and Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Roël van Orsoy
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - David Lamb
- Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Megan Webster
- Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Reinoud Gosens
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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18
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Ng B, Cook SA, Schafer S. Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway. Exp Mol Med 2020; 52:1871-1878. [PMID: 33262481 PMCID: PMC7705429 DOI: 10.1038/s12276-020-00531-5] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 01/16/2023] Open
Abstract
Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.
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Affiliation(s)
- Benjamin Ng
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.,Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Stuart A Cook
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.,Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.,MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, United Kingdom.,National Heart and Lung Institute, Imperial College, London, United Kingdom
| | - Sebastian Schafer
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore. .,Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
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19
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Cook SA, Schafer S. Hiding in Plain Sight: Interleukin-11 Emerges as a Master Regulator of Fibrosis, Tissue Integrity, and Stromal Inflammation. Annu Rev Med 2020; 71:263-276. [PMID: 31986085 DOI: 10.1146/annurev-med-041818-011649] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Interleukin (IL)-11 is upregulated in a wide variety of fibro-inflammatory diseases such as systemic sclerosis, rheumatoid arthritis, pulmonary fibrosis, inflammatory bowel disease, kidney disease, drug-induced liver injury, and nonalcoholic steatohepatitis. IL-11 is a member of the IL-6 cytokine family and has several distinct properties that define its unique and nonredundant roles in disease. The IL-11 receptor is highly expressed on stromal, epithelial and polarized cells, where noncanonical IL-11 signaling drives the three pathologies common to all fibro-inflammatory diseases-myofibroblast activation, parenchymal cell dysfunction, and inflammation-while also inhibiting tissue regeneration. This cytokine has been little studied, and publications on IL-11 peaked in the early 1990s, when it was largely misunderstood. Here we describe recent advances in our understanding of IL-11 biology, outline how misconceptions as to its function came about, and highlight the large potential of therapies targeting IL-11 signaling for treating human disease.
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Affiliation(s)
- Stuart A Cook
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 169857 Singapore, Singapore; , .,National Heart Research Institute Singapore, National Heart Centre Singapore, 169609 Singapore, Singapore.,National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.,MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, United Kingdom
| | - Sebastian Schafer
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 169857 Singapore, Singapore; , .,National Heart Research Institute Singapore, National Heart Centre Singapore, 169609 Singapore, Singapore
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20
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Ng B, Dong J, Viswanathan S, Widjaja AA, Paleja BS, Adami E, Ko NSJ, Wang M, Lim S, Tan J, Chothani SP, Albani S, Schafer S, Cook SA. Fibroblast-specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease. FASEB J 2020; 34:11802-11815. [PMID: 32656894 DOI: 10.1096/fj.202001045rr] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 11/08/2023]
Abstract
Repetitive pulmonary injury causes fibrosis and inflammation that underlies chronic lung diseases such as idiopathic pulmonary fibrosis (IPF). Interleukin 11 (IL11) is important for pulmonary fibroblast activation but the contribution of fibroblast-specific IL11 activity to lung fibro-inflammation is not known. To address this gap in knowledge, we generated mice with loxP-flanked Il11ra1 and deleted the IL11 receptor in adult fibroblasts (CKO mice). In the bleomycin (BLM) model of lung fibrosis, CKO mice had reduced fibrosis, lesser fibroblast ERK activation, and diminished immune cell STAT3 phosphorylation. Following BLM injury, acute inflammation in CKO mice was similar to controls but chronic immune infiltrates and pro-inflammatory gene activation, including NF-kB phosphorylation, were notably reduced. Therapeutic prevention of IL11 activity with neutralizing antibodies mirrored the effects of genetic deletion of Il11ra1 in fibroblasts. These data reveal a new function for IL11 in pro-inflammatory lung fibroblasts and highlight the important contribution of the stroma to inflammation in pulmonary disease.
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Affiliation(s)
- Benjamin Ng
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Jinrui Dong
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Sivakumar Viswanathan
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Anissa A Widjaja
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Bhairav S Paleja
- Translational Immunology Institute, SingHealth/Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Eleonora Adami
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Nicole S J Ko
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Mao Wang
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Stella Lim
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Jessie Tan
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Sonia P Chothani
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Salvatore Albani
- Translational Immunology Institute, SingHealth/Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Sebastian Schafer
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Stuart A Cook
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
- National Heart and Lung Institute, Imperial College, London, UK
- MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, UK
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21
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Lim WW, Ng B, Widjaja A, Xie C, Su L, Ko N, Lim SY, Kwek XY, Lim S, Cook SA, Schafer S. Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice. PLoS One 2020; 15:e0227505. [PMID: 31917819 PMCID: PMC6952089 DOI: 10.1371/journal.pone.0227505] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 12/19/2019] [Indexed: 01/19/2023] Open
Abstract
Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11SMC). Within days of transgene activation, Il11SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including the heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11Fib mouse. This additional model largely phenocopied the Il11SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn's disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease.
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Affiliation(s)
- Wei-Wen Lim
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Benjamin Ng
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Anissa Widjaja
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Chen Xie
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Liping Su
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Nicole Ko
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Sze-Yun Lim
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Xiu-Yi Kwek
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Stella Lim
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Stuart Alexander Cook
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
- National Heart and Lung Institute, Imperial College London, London, England, United Kingdom
- MRC-London Institute of Medical Sciences, London, England, United Kingdom
| | - Sebastian Schafer
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
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22
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Mukai K, Tsai M, Saito H, Galli SJ. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev 2019; 282:121-150. [PMID: 29431212 DOI: 10.1111/imr.12634] [Citation(s) in RCA: 486] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease.
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Affiliation(s)
- Kaori Mukai
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA
| | - Mindy Tsai
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA
| | - Hirohisa Saito
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health & Development, Tokyo, Japan
| | - Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA.,Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
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23
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Michalik M, Wójcik-Pszczoła K, Paw M, Wnuk D, Koczurkiewicz P, Sanak M, Pękala E, Madeja Z. Fibroblast-to-myofibroblast transition in bronchial asthma. Cell Mol Life Sci 2018; 75:3943-3961. [PMID: 30101406 PMCID: PMC6182337 DOI: 10.1007/s00018-018-2899-4] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 07/26/2018] [Accepted: 08/06/2018] [Indexed: 12/11/2022]
Abstract
Bronchial asthma is a chronic inflammatory disease in which bronchial wall remodelling plays a significant role. This phenomenon is related to enhanced proliferation of airway smooth muscle cells, elevated extracellular matrix protein secretion and an increased number of myofibroblasts. Phenotypic fibroblast-to-myofibroblast transition represents one of the primary mechanisms by which myofibroblasts arise in fibrotic lung tissue. Fibroblast-to-myofibroblast transition requires a combination of several types of factors, the most important of which are divided into humoural and mechanical factors, as well as certain extracellular matrix proteins. Despite intensive research on the nature of this process, its underlying mechanisms during bronchial airway wall remodelling in asthma are not yet fully clarified. This review focuses on what is known about the nature of fibroblast-to-myofibroblast transition in asthma. We aim to consider possible mechanisms and conditions that may play an important role in fibroblast-to-myofibroblast transition but have not yet been discussed in this context. Recent studies have shown that some inherent and previously undescribed features of fibroblasts can also play a significant role in fibroblast-to-myofibroblast transition. Differences observed between asthmatic and non-asthmatic bronchial fibroblasts (e.g., response to transforming growth factor β, cell shape, elasticity, and protein expression profile) may have a crucial influence on this phenomenon. An accurate understanding and recognition of all factors affecting fibroblast-to-myofibroblast transition might provide an opportunity to discover efficient methods of counteracting this phenomenon.
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Affiliation(s)
- Marta Michalik
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.
| | - Katarzyna Wójcik-Pszczoła
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
| | - Milena Paw
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Dawid Wnuk
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
| | - Paulina Koczurkiewicz
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Marek Sanak
- Division of Molecular Biology and Clinical Genetics, Department of Medicine, Jagiellonian University Medical College, Skawińska 8, 31-066, Kraków, Poland
| | - Elżbieta Pękala
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Zbigniew Madeja
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland
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24
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Deguchi Y, Nishina T, Asano K, Ohmuraya M, Nakagawa Y, Nakagata N, Sakuma T, Yamamoto T, Araki K, Mikami T, Tanaka M, Nakano H. Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice. Biochem Biophys Res Commun 2018; 505:453-459. [PMID: 30268501 DOI: 10.1016/j.bbrc.2018.09.128] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 09/19/2018] [Indexed: 10/28/2022]
Abstract
Interleukin (IL)-11 belongs to the members of the IL-6 family of cytokines and is involved in a variety of biological responses, including hematopoiesis, bone development, and carcinogenesis. However, the cellular sources of IL-11 and regulation of IL-11 expression under physiological and pathological conditions are not fully understood. One of the causes to prevent characterization of IL-11 in vivo is due to the lack of reliable antibodies that detect IL-11 by immunohistochemistry. Moreover, although mice lacking Il11ra have been generated and extensively characterized, Il11-deficient mice have not been characterized yet. Here we generated two anti-IL-11 antibodies that blocked biological activities of IL-11 and detected IL-11 by immunohistochemistry, respectively. One clone of anti-IL-11 antibodies blocked IL-11-, but not IL-6-induced cell proliferation and IL-11-induced phosphorylation of STAT3 of an IL-11-dependent cell line. Moreover, we used recently established Il11-deficient mice to test the specificity of anti-IL-11 antibodies for immunohistochemistry. Another clone of anti-IL-11 antibodies stained stromal cells surrounding tumors of the colon of wild-type, but not Il11-deficient mice following treatment with Azoxymethane plus dextran sulfate sodium. Together, these newly developed anti-IL-11 antibodies provide a better understanding of the functions of IL-11 in vivo under various physiological and pathological conditions.
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Affiliation(s)
- Yutaka Deguchi
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
| | - Takashi Nishina
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan.
| | - Kenichi Asano
- Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Masaki Ohmuraya
- Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yoshiko Nakagawa
- Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Naomi Nakagata
- Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Tetsushi Sakuma
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan
| | - Takashi Yamamoto
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan
| | - Kimi Araki
- Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Tetuo Mikami
- Department of Pathology, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
| | - Masato Tanaka
- Laboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Hiroyasu Nakano
- Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan; Host Defense Research Center, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan.
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25
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Ritchie AI, Singanayagam A, Wiater E, Edwards MR, Montminy M, Johnston SL. β 2-Agonists Enhance Asthma-Relevant Inflammatory Mediators in Human Airway Epithelial Cells. Am J Respir Cell Mol Biol 2018; 58:128-132. [PMID: 29286858 DOI: 10.1165/rcmb.2017-0315le] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Andrew I Ritchie
- 1 National Heart and Lung Institute, Imperial College London, United Kingdom.,2 Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma London, United Kingdom and
| | - Aran Singanayagam
- 1 National Heart and Lung Institute, Imperial College London, United Kingdom.,2 Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma London, United Kingdom and
| | | | - Michael R Edwards
- 1 National Heart and Lung Institute, Imperial College London, United Kingdom.,2 Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma London, United Kingdom and
| | | | - Sebastian L Johnston
- 1 National Heart and Lung Institute, Imperial College London, United Kingdom.,2 Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma London, United Kingdom and
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26
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Kim H, Ellis AK, Fischer D, Noseworthy M, Olivenstein R, Chapman KR, Lee J. Asthma biomarkers in the age of biologics. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2017; 13:48. [PMID: 29176991 PMCID: PMC5691861 DOI: 10.1186/s13223-017-0219-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 10/25/2017] [Indexed: 02/08/2023]
Abstract
The heterogeneous nature of asthma has been understood for decades, but the precise categorization of asthma has taken on new clinical importance in the era of specific biologic therapy. The simple categories of allergic and non-allergic asthma have given way to more precise phenotypes that hint at underlying biologic mechanisms of variable airflow limitation and airways inflammation. Understanding these mechanisms is of particular importance for the approximately 10% of patients with severe asthma. Biomarkers that aid in phenotyping allow physicians to "personalize" treatment with targeted biologic agents. Unfortunately, testing for these biomarkers is not routine in patients whose asthma is refractory to standard therapy. Scientific advances in the recognition of sensitive and specific biomarkers are steadily outpacing the clinical availability of reliable and non-invasive assessment methods designed for the prompt and specific diagnosis, classification, treatment, and monitoring of severe asthma patients. This article provides a practical overview of current biomarkers and testing methods for prompt, effective management of patients with severe asthma that is refractory to standard therapy.
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Affiliation(s)
- Harold Kim
- Division of Clinical Immunology & Allergy, Department of Medicine, Western University, 1151 Richmond St, London, ON N6A 5C1 Canada
- Division of Clinical Immunology & Allergy, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1 Canada
| | - Anne K. Ellis
- Division of Allergy & Immunology, Department of Medicine, Queen’s University, 15 Arch Street, Kingston, ON K7L 3N6 Canada
- Department of Biomedical and Molecular Sciences, School of Medicine, Queen’s University, Kingston, ON Canada
| | - David Fischer
- Division of Clinical Immunology & Allergy, Department of Medicine, Western University, 1151 Richmond St, London, ON N6A 5C1 Canada
- Canadian Society of Allergy and Clinical Immunology, P.O. Box 51045, Orleans, ON K1E 3W4 Canada
| | - Mary Noseworthy
- Alberta Children’s Hospital, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4 Canada
| | - Ron Olivenstein
- Division of Respiratory Medicine, Faculty of Medicine, McGill University, 3605 Rue De la Montagne, Montreal, QC H3G 2M1 Canada
- Acute Care Division, Montreal Chest Institute, 1001 Décarie Blvd, Montreal, QC H4A 3J1 Canada
| | - Kenneth R. Chapman
- Asthma and Airway Centre, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON M5T 2S8 Canada
- Division of Respirology, Department of Medicine, University of Toronto, 1 King’s College Circle, #3172, Toronto, ON M5S 1A8 Canada
| | - Jason Lee
- Toronto Allergy and Asthma Centre, 123 Edward St, Toronto, ON M5G 1E2 Canada
- Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 30 Bond St, Toronto, ON M5B 1W8 Canada
- Department of Surgery, School of Medicine, University of Toronto, 1 King’s College Circle, #3172, Toronto, ON M5S 1A8 Canada
- Evidence Based Medical Educator Inc., 123 Edward St., Suite 920, Toronto, ON M5G 1E2 Canada
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27
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Tang X, Nian H, Li X, Yang Y, Wang X, Xu L, Shi H, Yang X, Liu R. Effects of the combined extracts of Herba Epimedii and Fructus Ligustrilucidi on airway remodeling in the asthmatic rats with the treatment of budesonide. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:380. [PMID: 28764781 PMCID: PMC5540498 DOI: 10.1186/s12906-017-1891-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 07/24/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND Asthma is characterized by chronic airway inflammation, leading to structura1 changes in the airway, collectively termed airway remodeling. Airway remodeling is thought to contribute to airway hyper responsiveness and irreversible airflow limitation. The combination of Herba Epimedii (HE) and Fructus Ligustri Lucidi (FLL) decoction and the systemic administration of glucocorticoids (GC) had a synergistic inhibitory action on airway inflammation in the asthmatic model rats. However, the effects of the combination on airway remodeling have not been studied and compared. In the present study, we investigated the effects of the co-administration of combined extracts of HE and FLL with inhaled GC (budesonide) on airway remodeling in the rat asthmatic model induced by ovalbumin (OVA). METHODS Male Sprague-Dawley rats were sensitized to intraperitoneal OVA followed by repetitive OVA challenge for 7 weeks. Treatments included extracts of HE and FLL (Extracts for short, 100 mg/kg by gastric perfusion), budesonide (1 mg budesonide suspension in 50 ml sterile physiological saline, 3 rats in an ultrasonic nebulizer by nebulized inhabation with a flow of 1.6 ml/min for 30 min), and co-administration of extracts of HE and FLL with budesonide (Co-administration for short) for 4 weeks. Lung histomorphometry and bronchoalveolar lavage fluid (BALF) cell count were assessed 24 h after the final OVA challenge. Levels of interleukin (IL)-4, IL-5 and IgE were measured by ELISA. Expressions of Collagen I and Collagen III were tested by immunohistology. Expressions of transforming growth factor (TGF) -β1, TGF-β2 and Smads mRNA were measured by quantitative real-time PCR. RESULTS Extracts, budesonide and Co-administration significantly reduced allergen-induced increases in the serum levels of IL-4, IL-5 and IgE, the number of eosinophils in BALF, goblet cell hyperplasia, Collagen III integral optical density (IOD) and the mRNA expression of TGF-β2 and Smad2. Extracts and Co-administration could depress the IOD level of Collagen I and the positive area of Collagen I and Collagen III. Budesonide and Co-administration significantly alleviated the thickening of airway wall. Only Co-administration significantly decreased collagen deposition according to the morphometry of Masson's-stained lung sections, the thickening of airway smooth muscle layer, the number of lymphocytes in BALF and the mRNA expression of TGF-β1 and Smad3, and this was associated with a significant increase in levels of Smad7 mRNA. CONCLUSIONS The findings suggested that the combination of budesonide and the herbal extracts had a better synergistic effect on airway remodeling in OVA-reduced asthma rats than the single use of budesonide.
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Affiliation(s)
- Xiufeng Tang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Honglei Nian
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Xiaoxi Li
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Yan Yang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Xiujuan Wang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Liping Xu
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Haotian Shi
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Xinwei Yang
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
| | - Renhui Liu
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, No.10 Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069 China
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Pelaia G, Vatrella A, Busceti MT, Fabiano F, Terracciano R, Matera MG, Maselli R. Molecular and cellular mechanisms underlying the therapeutic effects of budesonide in asthma. Pulm Pharmacol Ther 2016; 40:15-21. [PMID: 27381656 DOI: 10.1016/j.pupt.2016.07.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/04/2016] [Accepted: 07/01/2016] [Indexed: 02/07/2023]
Abstract
Inhaled glucocorticoids are the mainstay of asthma treatment. Indeed, such therapeutic agents effectively interfere with many pathogenic circuits underpinning asthma. Among these drugs, during the last decades budesonide has been probably the most used molecule in both experimental studies and clinical practice. Therefore, a large body of evidence clearly shows that budesonide, either alone or in combination with long-acting bronchodilators, provides a successful control of asthma in many patients ranging throughout the overall spectrum of disease severity. These excellent therapeutic properties of budesonide basically depend on its molecular mechanisms of action, capable of inhibiting within the airways the activity of multiple immune-inflammatory and structural cells involved in asthma pathobiology.
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Affiliation(s)
- Girolamo Pelaia
- Department of Medical and Surgical Sciences, Section of Respiratory Diseases, University "Magna Græcia" of Catanzaro, Italy.
| | - Alessandro Vatrella
- Department of Medicine and Surgery, Section of Respiratory Diseases, University of Salerno, Italy
| | - Maria Teresa Busceti
- Department of Medical and Surgical Sciences, Section of Respiratory Diseases, University "Magna Græcia" of Catanzaro, Italy
| | - Francesco Fabiano
- Pulmonary Rehabilitation, "Fondazione Don Carlo Gnocchi", Milan, Italy
| | - Rosa Terracciano
- Department of Health Science, University "Magna Græcia" of Catanzaro, Italy
| | - Maria Gabriella Matera
- Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Italy
| | - Rosario Maselli
- Department of Medical and Surgical Sciences, Section of Respiratory Diseases, University "Magna Græcia" of Catanzaro, Italy
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Lokau J, Nitz R, Agthe M, Monhasery N, Aparicio-Siegmund S, Schumacher N, Wolf J, Möller-Hackbarth K, Waetzig GH, Grötzinger J, Müller-Newen G, Rose-John S, Scheller J, Garbers C. Proteolytic Cleavage Governs Interleukin-11 Trans-signaling. Cell Rep 2016; 14:1761-1773. [PMID: 26876177 DOI: 10.1016/j.celrep.2016.01.053] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/22/2015] [Accepted: 01/14/2016] [Indexed: 12/22/2022] Open
Abstract
Interleukin (IL)-11 has been shown to be a crucial factor for intestinal tumorigenesis, lung carcinomas, and asthma. IL-11 is thought to exclusively mediate its biological functions through cell-type-specific expression of the membrane-bound IL-11 receptor (IL-11R). Here, we show that the metalloprotease ADAM10, but not ADAM17, can release the IL-11R ectodomain. Chimeric proteins of the IL-11R and the IL-6 receptor (IL-6R) revealed that a small juxtamembrane portion is responsible for this substrate specificity of ADAM17. Furthermore, we show that the serine proteases neutrophil elastase and proteinase 3 can also cleave the IL-11R. The resulting soluble IL-11R (sIL-11R) is biologically active and binds IL-11 to activate cells. This IL-11 trans-signaling pathway can be inhibited specifically by the anti-inflammatory therapeutic compound sgp130Fc. In conclusion, proteolysis of the IL-11R represents a molecular switch that controls the IL-11 trans-signaling pathway and widens the number of cells that can be activated by IL-11.
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Affiliation(s)
- Juliane Lokau
- Institute of Biochemistry, Kiel University, 24098 Kiel, Germany
| | - Rebecca Nitz
- Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Maria Agthe
- Institute of Biochemistry, Kiel University, 24098 Kiel, Germany
| | - Niloufar Monhasery
- Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | | | | | - Janina Wolf
- Institute of Biochemistry, Kiel University, 24098 Kiel, Germany
| | | | | | | | - Gerhard Müller-Newen
- Institute of Biochemistry and Molecular Biology, RWTH Aachen, 52074 Aachen, Germany
| | | | - Jürgen Scheller
- Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
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Davoine F, Lacy P. Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Front Immunol 2014; 5:570. [PMID: 25426119 PMCID: PMC4225839 DOI: 10.3389/fimmu.2014.00570] [Citation(s) in RCA: 215] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 10/24/2014] [Indexed: 12/30/2022] Open
Abstract
Eosinophils derive from the bone marrow and circulate at low levels in the blood in healthy individuals. These granulated cells preferentially leave the circulation and marginate to tissues, where they are implicated in the regulation of innate and adaptive immunity. In diseases such as allergic inflammation, eosinophil numbers escalate markedly in the blood and tissues where inflammatory foci are located. Eosinophils possess a range of immunomodulatory factors that are released upon cell activation, including over 35 cytokines, growth factors, and chemokines. Unlike T and B cells, eosinophils can rapidly release cytokines within minutes in response to stimulation. While some cytokines are stored as pre-formed mediators in crystalloid granules and secretory vesicles, eosinophils are also capable of undergoing de novo synthesis and secretion of these immunological factors. Some of the molecular mechanisms that coordinate the final steps of cytokine secretion are hypothesized to involve binding of membrane fusion complexes comprised of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs). These intracellular receptors regulate the release of granules and vesicles containing a range of secreted proteins, among which are cytokines and chemokines. Emerging evidence from both human and animal model-based research has suggested an active participation of eosinophils in several physiological/pathological processes such as immunomodulation and tissue remodeling. The observed eosinophil effector functions in health and disease implicate eosinophil cytokine secretion as a fundamental immunoregulatory process. The focus of this review is to describe the cytokines, growth factors, and chemokines that are elaborated by eosinophils, and to illustrate some of the intracellular events leading to the release of eosinophil-derived cytokines.
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Affiliation(s)
- Francis Davoine
- Pulmonary Research Group, Department of Medicine, University of Alberta , Edmonton, AB , Canada
| | - Paige Lacy
- Pulmonary Research Group, Department of Medicine, University of Alberta , Edmonton, AB , Canada
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31
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Reeves SR, Kolstad T, Lien TY, Elliott M, Ziegler SF, Wight TN, Debley JS. Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components. J Allergy Clin Immunol 2014; 134:663-670.e1. [PMID: 24875618 DOI: 10.1016/j.jaci.2014.04.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 04/06/2014] [Accepted: 04/11/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Airway remodeling might explain lung function decline among asthmatic children. Extracellular matrix (ECM) deposition by human lung fibroblasts (HLFs) is implicated in airway remodeling. Airway epithelial cell (AEC) signaling might regulate HLF ECM expression. OBJECTIVES We sought to determine whether AECs from asthmatic children differentially regulate HLF expression of ECM constituents. METHODS Primary AECs were obtained from well-characterized atopic asthmatic (n = 10) and healthy (n = 10) children intubated during anesthesia for an elective surgical procedure. AECs were differentiated at an air-liquid interface for 3 weeks and then cocultured with HLFs from a healthy child for 96 hours. Collagen I (COL1A1), collagen III (COL3A1), hyaluronan synthase (HAS) 2, and fibronectin expression by HLFs and prostaglandin E2 synthase (PGE2S) expression by AECs were assessed by using RT-PCR. TGF-β1 and TGF-β2 concentrations in media were measured by using ELISA. RESULTS COL1A1 and COL3A1 expression by HLFs cocultured with AECs from asthmatic patients was greater than that by HLFs cocultured with AECs from healthy subjects (2.2-fold, P < .02; 10.8-fold, P < .02). HAS2 expression by HLFs cocultured with AECs from asthmatic patients was 2.5-fold higher than that by HLFs cocultured with AECs from healthy subjects (P < .002). Fibronectin expression by HLFs cocultured with AECs from asthmatic patients was significantly greater than that by HLFs alone. TGF-β2 activity was increased in cocultures of HLFs with AECs from asthmatic patients (P < .05), whereas PGES2 was downregulated in AEC-HLF cocultures (2.2-fold, P < .006). CONCLUSIONS HLFs cocultured with AECs from asthmatic patients showed differential expression of the ECM constituents COL1A1 and COL3A1 and HAS2 compared with HLFs cocultured with AECs from healthy subjects. These findings support a role for altered ECM production in asthmatic airway remodeling, possibly regulated by unbalanced AEC signaling.
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Affiliation(s)
- Stephen R Reeves
- Division of Pulmonary Medicine, Seattle Children's Hospital, University of Washington, Seattle, Wash; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash
| | - Tessa Kolstad
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash
| | - Tin-Yu Lien
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash
| | - Molly Elliott
- Division of Pulmonary Medicine, Seattle Children's Hospital, University of Washington, Seattle, Wash; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash
| | | | | | - Jason S Debley
- Division of Pulmonary Medicine, Seattle Children's Hospital, University of Washington, Seattle, Wash; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash.
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Persson C, Uller L. Theirs but to die and do: primary lysis of eosinophils and free eosinophil granules in asthma. Am J Respir Crit Care Med 2014; 189:628-33. [PMID: 24512466 DOI: 10.1164/rccm.201311-2069oe] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Carl Persson
- 1 Department of Clinical Pharmacology, Laboratory Medicine, Lund University Hospital, Lund, Sweden; and
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Layachi S, Porra L, Albu G, Trouillet N, Suhonen H, Peták F, Sevestre H, Suortti P, Sovijärvi A, Habre W, Bayat S. Role of cellular effectors in the emergence of ventilation defects during allergic bronchoconstriction. J Appl Physiol (1985) 2013; 115:1057-64. [PMID: 23887899 DOI: 10.1152/japplphysiol.00844.2012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
It is not known whether local factors within the airway wall or parenchyma may influence the emergence and spatial distribution of ventilation defects (VDs), thereby modulating the dynamic system behavior of the lung during bronchoconstriction. We assessed the relationship between the distribution of cellular effectors and the emergence of defects in regional ventilation distribution following allergen challenge. We performed high-resolution K-edge subtraction (KES) synchrotron imaging during xenon inhalation and measured the forced oscillatory input impedance in ovalbumin (OVA)-sensitized Brown-Norway rats (n = 12) at baseline and repeatedly following OVA challenge. Histological slices with best anatomic matching to the computed tomographic images were stained with a modified May-Grunwald Giemsa and immunohistochemical staining with monoclonal anti-rat CD68, in six rats. Slides were digitized and total cells and eosinophils were counted in the walls of bronchi and vessels randomly selected within and outside of VDs on the basis of xenon-KES images. Ventilated alveolar area decreased and ventilation heterogeneity, Newtonian resistance, tissue damping, and elastance increased following OVA challenge. Eosinophil, total cell, and CD68+ counts were significantly higher in the bronchial and vascular walls within vs. outside of the VDs. The minimal central airway diameters during OVA-induced bronchoconstriction were correlated with eosinophil (R = -0.85; P = 0.031) and total cell densities (R = -0.82; P = 0.046) in the airway walls within the poorly ventilated zones. Our findings suggest that allergic airway inflammation is locally heterogeneous and is topographically associated with the local emergence of VDs following allergen challenge.
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Affiliation(s)
- Skander Layachi
- Université de Picardie Jules Verne and Amiens University Hospital, Amiens, France
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Nogueira-Silva C, Piairo P, Carvalho-Dias E, Veiga C, Moura RS, Correia-Pinto J. The role of glycoprotein 130 family of cytokines in fetal rat lung development. PLoS One 2013; 8:e67607. [PMID: 23826327 PMCID: PMC3691159 DOI: 10.1371/journal.pone.0067607] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Accepted: 05/24/2013] [Indexed: 11/24/2022] Open
Abstract
The glycoprotein 130 (gp130) dependent family of cytokines comprises interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and oncostatin M (OSM). These cytokines share the membrane gp130 as a common signal transducer. Recently, it was demonstrated that IL-6 promotes, whereas LIF inhibits fetal lung branching. Thus, in this study, the effects on fetal lung morphogenesis of the other classical members of the gp130-type cytokines (IL-11, CLC, CNTF, CT-1 and OSM) were investigated. We also provide the first description of these cytokines and their common gp130 receptor protein expression patterns during rat lung development. Fetal rat lung explants were cultured in vitro with increasing concentrations of IL-11, CLC, CNTF, CT-1 and OSM. Treated lung explants were morphometrically analyzed and assessed for MAPK, PI3K/AKT and STAT3 signaling modifications. IL-11, which similarly to IL-6 acts through a gp130 homodimer receptor, significantly stimulated lung growth via p38 phosphorylation. On the other hand, CLC, CNTF, CT-1 and OSM, whose receptors are gp130 heterodimers, inhibited lung growth acting in different signal-transducing pathways. Thus, the present study demonstrated that although cytokines of the gp130 family share a common signal transducer, there are specific biological activities for each cytokine on lung development. Indeed, cytokine signaling through gp130 homodimers stimulate, whereas cytokine signaling through gp130 heterodimers inhibit lung branching.
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Affiliation(s)
- Cristina Nogueira-Silva
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Department of Obstetrics and Gynecology, Hospital de Braga, Braga, Portugal
| | - Paulina Piairo
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Emanuel Carvalho-Dias
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Department of Urology, Hospital de Braga, Braga, Portugal
| | - Carla Veiga
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rute S. Moura
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Jorge Correia-Pinto
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Department of Pediatric Surgery, Hospital de Braga, Braga, Portugal
- * E-mail:
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Al-Muhsen S, Letuve S, Vazquez-Tello A, Pureza MA, Al-Jahdali H, Bahammam AS, Hamid Q, Halwani R. Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils. Respir Res 2013; 14:34. [PMID: 23496774 PMCID: PMC3602055 DOI: 10.1186/1465-9921-14-34] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 03/07/2013] [Indexed: 01/08/2023] Open
Abstract
Background Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood. Objective In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines. Methods Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-β and IL-11 was determined using real time PCR and ELISA assays. Results The basal expression levels of eosinophil derived TGF-β and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-β and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release. Conclusions Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases.
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Affiliation(s)
- Saleh Al-Muhsen
- Asthma Research Chair and Prince Naif Center for Immunology Research, Department of Paediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Gibeon D, Menzies-Gow AN. Targeting interleukins to treat severe asthma. Expert Rev Respir Med 2013; 6:423-39. [PMID: 22971067 DOI: 10.1586/ers.12.38] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Severe asthma is thought to be a heterogeneous disease with different phenotypes predicated primarily on the nature of the inflammatory cell infiltrate and response to corticosteroid therapy. This group of patients often has refractory disease with an associated increase in morbidity and mortality, and there remains a need for better therapies for severe asthmatics. Inflammatory changes in asthma are driven by immune mechanisms, within which interleukins play an integral role. Interleukins are cell-signaling cytokines that are produced by a variety of cells, predominantly T cells. Knowledge about their actions has improved the understanding of the pathogenesis of asthma and provided potential targets for novel therapies. To date, this has not translated into clinical use. However, there are ongoing clinical trials that use monoclonal antibodies for various interleukins, some of which have shown to be promising in Phase II studies.
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Ghosh S, Hoselton SA, Dorsam GP, Schuh JM. Eosinophils in fungus-associated allergic pulmonary disease. Front Pharmacol 2013; 4:8. [PMID: 23378838 PMCID: PMC3561640 DOI: 10.3389/fphar.2013.00008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 01/10/2013] [Indexed: 12/30/2022] Open
Abstract
Asthma is frequently caused and/or exacerbated by sensitization to fungal allergens, which are ubiquitous in many indoor and outdoor environments. Severe asthma with fungal sensitization is characterized by airway hyperresponsiveness and bronchial constriction in response to an inhaled allergen that is worsened by environmental exposure to airborne fungi and which leads to a disease course that is often very difficult to treat with standard asthma therapies. As a result of complex interactions among inflammatory cells, structural cells, and the intercellular matrix of the allergic lung, patients with sensitization to fungal allergens may experience a greater degree of airway wall remodeling and progressive, accumulated pulmonary dysfunction as part of the disease sequela. From their development in the bone marrow to their recruitment to the lung via chemokine and cytokine networks, eosinophils form an important component of the inflammatory milieu that is associated with this syndrome. Eosinophils are recognized as complex multi-factorial leukocytes with diverse functions in the context of allergic fungal asthma. In this review, we will consider recent advances in our understanding of the molecular mechanisms that are associated with eosinophil development and migration to the allergic lung in response to fungal inhalation, along with the eosinophil’s function in the immune response to and the immunopathology attributed to fungus-associated allergic pulmonary disease.
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Affiliation(s)
- Sumit Ghosh
- Department of Veterinary and Microbiological Sciences, North Dakota State University Fargo, ND, USA
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Lecureur V, Arzel M, Ameziane S, Houlbert N, Le Vee M, Jouneau S, Fardel O. MAPK- and PKC/CREB-dependent induction of interleukin-11 by the environmental contaminant formaldehyde in human bronchial epithelial cells. Toxicology 2012; 292:13-22. [DOI: 10.1016/j.tox.2011.11.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 11/10/2011] [Accepted: 11/17/2011] [Indexed: 01/05/2023]
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Roth N, Städler S, Lemann M, Hösli S, Simon HU, Simon D. Distinct eosinophil cytokine expression patterns in skin diseases - the possible existence of functionally different eosinophil subpopulations. Allergy 2011; 66:1477-86. [PMID: 21884530 DOI: 10.1111/j.1398-9995.2011.02694.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The function of eosinophils has been attributed to host defense, immunomodulation, and fibrosis. Although eosinophils are found among infiltrating cells in a broad spectrum of skin diseases, their pathogenic role remains uncertain. This study aimed to analyze the cytokine expression by eosinophils in different skin diseases. METHODS Skin specimens from different skin diseases [allergic/reactive, infectious, autoimmune, and tumors/lymphomas (LY)] were stained by antibodies directed to eosinophil cationic protein, cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-10, IL-11, IL-13, IL-17, IL-25, IL-33, interferon-γ, transforming growth factor (TGF)-β, and thymic stromal lymphopoietin], eotaxins (CCL11, CCL24, and CCL26), metalloproteinase (MMP)-9 as well as extracellular matrix proteins (tenascin-C and procollagen-3) and then analyzed by laser scanning microscopy. RESULTS The number of eosinophils varied considerably in and between disease groups and did not correlate with the numbers of accompanying inflammatory cells. The expression of IL-5, IL-6, IL-11, TGF-β, CCL24, and MMP-9 by eosinophils significantly differed between disease groups. Eosinophils in tumors/LY predominantly expressed IL-6, TGF-β, and CCL24, but not IL-11. On the other hand, in autoimmune diseases, eosinophils largely contributed to MMP-9 production. IL-5-generating eosinophils were particularly obvious in allergic and infectious diseases. CONCLUSION In skin diseases, eosinophil expresses a broad spectrum of cytokines. The different cytokine expression patterns suggest distinct functional roles of eosinophils in these diseases that might be related to host defense, immunomodulation, fibrosis, and/or tumor development.
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Affiliation(s)
- N Roth
- Department of Dermatology, Inselspital, Bern University Hospital, Switzerland
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Abstract
The airway epithelial cell is the initial cell type impacted both by inhaled environmental factors, such as pathogens, allergens, and pollutants, and inhaled medications for airway diseases. As such, epithelial cells are now recognized to play a central role in the regulation of airway inflammatory status, structure, and function in normal and diseased airways. This article reviews our current knowledge regarding the roles of the epithelial cell in airway inflammation and host defense. The interactions of inhaled environmental factors and pathogens with epithelial cells are also discussed, with an emphasis on epithelial innate immune responses and contributions of epithelial cells to immune regulation. Recent evidence suggesting that epithelial cells play an active role in inducing several of the structural changes, collectively referred to airway remodeling, seen in the airways of asthmatic subjects is reviewed. Finally, the concept that the epithelium is a major target for the actions of a number of classes of inhaled medications is discussed, as are the potential mechanisms by which selected drugs may alter epithelial function.
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Affiliation(s)
- David Proud
- Department of Physiology and Pharmacology, University of Calgary Faculty of Medicine, Calgary, AB, Canada.
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Nagashima H, Nakamura Y, Kanno H, Sawai T, Inoue H, Yamauchi K. Effect of genetic variation of IL-13 on airway remodeling in bronchial asthma. Allergol Int 2011; 60:291-8. [PMID: 21430433 DOI: 10.2332/allergolint.10-oa-0259] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2010] [Accepted: 10/29/2010] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND IL-13 is a major stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13Q110 is the non-conservative replacement of a positively charged arginine (R) with a neutral glutamine (Q) at position 110 of IL-13, and as we already know, individuals homozygous for glutamine (Q110/Q110) are strongly associated with asthma and IgE. IL13Q110 has been demonstrated to show that increased allergic inflammation depended on the enhanced IL-13-mediated Th2 effector function. Therefore, we investigated whether Q110/Q110 accelerated the decline in pulmonary function and development of airway remodeling of asthmatic patients in the general population. METHODS A total 336 asthmatic subjects living in Japan were recruited, genotyped, and had a pulmonary function test performed on them. To analyze airway inflammation and remodeling, bronchial lavage fluid (BLF) and endobronchial biopsy specimens were examined. RESULTS Forced expiratory volume in one second (FEV1), %predicted, forced expiratory volume/forced vital capacity ratio, and forced expiratory flow 25-75%, % predicted were significantly decreased in Q110/Q110 compared to R110/R110, and the decline in FEV1 was increased significantly in Q110/Q110 compared to R110/R110. The concentration of IL-13, IL-23, IL-11, GM-CSF, hyaluronic acid, and CCL8 in BLF were increased in Q110/Q110 compared to R110/R110 and the thickness of the subepithelial layer was thicker. CONCLUSIONS Our study demonstrates that Q110/Q110 increases, at least in part, allergic inflammation and the propensity for airway remodeling, thus resulting in low lung function.
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Affiliation(s)
- Hiromi Nagashima
- Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Japan
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Al-Muhsen S, Johnson JR, Hamid Q. Remodeling in asthma. J Allergy Clin Immunol 2011; 128:451-62; quiz 463-4. [PMID: 21636119 DOI: 10.1016/j.jaci.2011.04.047] [Citation(s) in RCA: 311] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 04/22/2011] [Accepted: 04/26/2011] [Indexed: 01/26/2023]
Abstract
Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways. Airway remodeling in asthmatic patients involves a wide array of pathophysiologic features, including epithelial changes, increased smooth muscle mass, increased numbers of activated fibroblasts/myofibroblasts, subepithelial fibrosis, and vascular changes. Multiple cytokines, chemokines, and growth factors released from both inflammatory and structural cells in the airway tissue create a complex signaling environment that drives these structural changes. However, recent investigations have changed our understanding of asthma from a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Several reports have suggested that asthma primarily develops because of serious defects in the epithelial layer that allow environmental allergens, microorganisms, and toxins greater access to the airway tissue and that can also stimulate the release of mediators from the epithelium, thus contributing to tissue remodeling. Lung-resident fibroblasts and smooth muscle cells have also been implicated in the pathogenesis of airway remodeling. Remodeling is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness. Asthmatic subjects experience an accelerated decrease in lung function compared with healthy subjects, which is proportionally related to the duration and severity of their disease.
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Affiliation(s)
- Saleh Al-Muhsen
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Shamri R, Xenakis JJ, Spencer LA. Eosinophils in innate immunity: an evolving story. Cell Tissue Res 2010; 343:57-83. [PMID: 21042920 DOI: 10.1007/s00441-010-1049-6] [Citation(s) in RCA: 155] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 09/01/2010] [Indexed: 12/27/2022]
Abstract
Eosinophils are innate immune leukocytes found in relatively low numbers within the blood. Terminal effector functions of eosinophils, deriving from their capacity to release their content of tissue-destructive cationic proteins, have historically been considered primary effector mechanisms against specific parasites, and are likewise implicated in tissue damage accompanying allergic responses such as asthma. However, the past decade has seen dramatic advancements in the field of eosinophil immunobiology, revealing eosinophils to also be key participants in many other facets of innate immunity, from bridging innate and adaptive immune responses to orchestrating tissue remodeling events. Here, we review the multifaceted functions of eosinophils in innate immunity that are currently known, and discuss new avenues in this evolving story.
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Affiliation(s)
- Revital Shamri
- Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Bergeron C, Tulic MK, Hamid Q. Airway remodelling in asthma: from benchside to clinical practice. Can Respir J 2010; 17:e85-93. [PMID: 20808979 PMCID: PMC2933777 DOI: 10.1155/2010/318029] [Citation(s) in RCA: 213] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Airway remodelling refers to the structural changes that occur in both large and small airways relevant to miscellaneous diseases including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, gland enlargement, neovascularization and epithelial alterations. Although controversial, airway remodelling is commonly attributed to an underlying chronic inflammatory process. These remodelling changes contribute to thickening of airway walls and, consequently, lead to airway narrowing, bronchial hyper-responsiveness, airway edema and mucous hypersecretion. Airway remodelling is associated with poor clinical outcomes among asthmatic patients. Early diagnosis and prevention of airway remodelling has the potential to decrease disease severity, improve control and prevent disease expression. The relationship between structural changes and clinical and functional abnormalities clearly deserves further investigation. The present review briefly describes the characteristic features of airway remodelling observed in asthma, its clinical consequences and relevance for physicians, and its modulation by therapeutic approaches used in the treatment of asthmatic patients.
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Affiliation(s)
- Céline Bergeron
- Hotel-Dieu Hospital, Centre Hospitalier de l’Université de Montréal, University of Montreal, Montreal, Quebec
| | - Meri K Tulic
- Division of Cell Biology, Telethon Institute for Child Health Research, Centre for Child Health Research, Perth, Australia
| | - Qutayba Hamid
- Meakins-Christie Laboratories, McGilll University, Montreal, Quebec
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Fritz DK, Kerr C, Botelho F, Stampfli M, Richards CD. Oncostatin M (OSM) primes IL-13- and IL-4-induced eotaxin responses in fibroblasts: Regulation of the type-II IL-4 receptor chains IL-4Rα and IL-13Rα1. Exp Cell Res 2009; 315:3486-99. [DOI: 10.1016/j.yexcr.2009.09.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2009] [Revised: 09/10/2009] [Accepted: 09/24/2009] [Indexed: 01/13/2023]
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Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol 2009; 125:S53-72. [PMID: 19932918 DOI: 10.1016/j.jaci.2009.07.008] [Citation(s) in RCA: 282] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2009] [Revised: 07/09/2009] [Accepted: 07/10/2009] [Indexed: 02/07/2023]
Abstract
Cytokines and chemokines are secreted proteins involved in numerous aspects of cell growth, differentiation, and activation. A prominent feature of these molecules is their effect on the immune system with regard to cell trafficking and development of immune tissue and organs. The nature of an immune response determines which cytokines are produced and ultimately whether the response is cytotoxic, humoral, cell mediated, or allergic. For this chapter, cytokines are grouped according to those that are predominantly antigen-presenting cell or T lymphocyte derived; that mediate cytotoxic, humoral, cell mediated, and allergic immunity; or that are immunosuppressive. A discussion of chemokine function and their role in cell trafficking and disease follows.
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Abstract
Asthma is characterized by chronic inflammation of the airways in which there is an overabundance of eosinophils, mast cells, and activated T helper lymphocytes. These inflammatory cells release mediators that then trigger bronchoconstriction, mucus secretion, and remodeling. The inflammatory mediators that drive this process include cytokines, chemokines, growth factors, lipid mediators, immunoglobulins, and histamine. The inflammation in allergic asthma can be difficult to control. This is mainly due to the development of an adaptive immunity to an allergen, leading to immunological memory. This leads to recall reactions to the allergen, causing persistent inflammation and damage to the airways. Generally, in asthma inflammation is directed by Th2 cytokines, which can act by positive feedback mechanisms to promote the production of more inflammatory mediators including other cytokines and chemokines. This review discusses the role of cytokines and chemokines in the immunobiology of asthma and attempts to relate their expression to morphological and functional abnormalities in the lungs of asthmatic subjects. We also discuss new concepts in asthma immunology, in particular the role of cytokines in airway remodeling and the interaction between cytokines and infection.
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Affiliation(s)
- Qutayba Hamid
- Meakins-Christie Labs, McGill University, Montreal, Québec H2X 2P2, Canada.
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Kawaguchi M, Fujita J, Kokubu F, Huang SK, Homma T, Matsukura S, Adachi M, Hizawa N. IL-17F-induced IL-11 release in bronchial epithelial cells via MSK1-CREB pathway. Am J Physiol Lung Cell Mol Physiol 2009; 296:L804-10. [PMID: 19251839 DOI: 10.1152/ajplung.90607.2008] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
IL-17F is involved in asthma, but its biological function and signaling pathway have not been fully elucidated. IL-11 is clearly expressed in the airway of patients with allergic airway diseases such as asthma and plays an important role in airway remodeling and inflammation. Therefore, we investigated the expression of IL-11 by IL-17F in bronchial epithelial cells. Bronchial epithelial cells were cultured in the presence or absence of IL-17F and/or Th2 cytokines (IL-4 and IL-13) or various kinase inhibitors to analyze the expression of IL-11. Next, activation of mitogen- and stress-activated protein kinase (MSK) 1 by IL-17F was investigated. Moreover, the effect of short interfering RNAs (siRNAs) targeting MSK1 and cAMP response element binding protein (CREB) on IL-17F-induced IL-11 expression was investigated. IL-17F induced IL-11 expression, whereas the costimulation with IL-4 and IL-13 augmented this effect even further. MEK inhibitors PD-98059, U0126, and Raf1 kinase inhibitor I, significantly inhibited IL-11 production, whereas overexpression of a Raf1 dominant-negative mutant inhibited its expression. IL-17F clearly phosphorylated MSK1, whereas PD-98059 inhibited the phosphorylation of IL-17F-induced MSK1. Both MSK1 inhibitors Ro-31-8220 and H89 significantly blocked IL-11 expression. Moreover, transfection of the cells with siRNAs targeting MSK1 inhibited activation of CREB, and the siRNAs targeting MSK1 and CREB blocked expression of IL-11. These data suggest that IL-17F may be involved in airway inflammation and remodeling via the induction of IL-11, and RafI-MEK1/2-ERK1/2-MSK1-CREB is identified as a novel signaling pathway participating in this process. Therefore, the IL-17F/IL-11 axis may be a valuable therapeutic target for asthma.
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Affiliation(s)
- Mio Kawaguchi
- Department of Respiratory Medicine, University of Tsukuba, Ibaraki 3058575, Japan.
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Lee CG, Hartl D, Matsuura H, Dunlop FM, Scotney PD, Fabri LJ, Nash AD, Chen NY, Tang CY, Chen Q, Homer RJ, Baca M, Elias JA. Endogenous IL-11 signaling is essential in Th2- and IL-13-induced inflammation and mucus production. Am J Respir Cell Mol Biol 2008; 39:739-46. [PMID: 18617680 DOI: 10.1165/rcmb.2008-0053oc] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
IL-11 and IL-11 receptor (R)alpha are induced by Th2 cytokines. However, the role(s) of endogenous IL-11 in antigen-induced Th2 inflammation has not been fully defined. We hypothesized that IL-11, signaling via IL-11Ralpha, plays an important role in aeroallergen-induced Th2 inflammation and mucus metaplasia. To test this hypothesis, we compared the responses induced by the aeroallergen ovalbumin (OVA) in wild-type (WT) and IL-11Ralpha-null mutant mice. We also generated and defined the effects of an antagonistic IL-11 mutein on pulmonary Th2 responses. Increased levels of IgE, eosinophilic tissue and bronchoalveolar lavage (BAL) inflammation, IL-13 production, and increased mucus production and secretion were noted in OVA-sensitized and -challenged WT mice. These responses were at least partially IL-11 dependent because each was decreased in mice with null mutations of IL-11Ralpha. Importantly, the administration of the IL-11 mutein to OVA-sensitized mice before aerosol antigen challenge also caused a significant decrease in OVA-induced inflammation, mucus responses, and IL-13 production. Intraperitoneal administration of the mutein to lung-specific IL-13-overexpressing transgenic mice also reduced BAL inflammation and airway mucus elaboration. These studies demonstrate that endogenous IL-11R signaling plays an important role in antigen-induced sensitization, eosinophilic inflammation, and airway mucus production. They also demonstrate that Th2 and IL-13 responses can be regulated by interventions that manipulate IL-11 signaling in the murine lung.
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Affiliation(s)
- Chun Geun Lee
- Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
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