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World J Stem Cells. Sep 26, 2017; 9(9): 152-158
Published online Sep 26, 2017. doi: 10.4252/wjsc.v9.i9.152
Role of aryl hydrocarbon receptor in mesenchymal stromal cell activation: A minireview
Danilo Candido de Almeida, Laura Sibele Martins Evangelista, Niels Olsen Saraiva Câmara, Department of Medicine, Nephrology Division, Federal University of São Paulo, São Paulo, SP 04039-003, Brazil
Niels Olsen Saraiva Câmara, Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, SP 05508-000, Brazil
Author contributions: de Almeida DC and Evangelista LSM wrote the manuscript; Câmara NOS contributed to extensive review and supervision.
Supported by São Paulo Research Public Foundation FAPESP and National Counsel of Technological and Scientific Development CNPq, No. 07/07193-3 and No. 12/02270-2.
Conflict-of-interest statement: The authors declare no potential conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Danilo Candido de Almeida, PhD, Affiliate Professor, Department of Medicine, Nephrology Division, Federal University of São Paulo, Rua Pedro de Toledo, 669 - 10 Andar - Frente, Vila Clementino, São Paulo, SP 04039-003, Brazil.
Telephone: +55-11-55764841
Received: March 29, 2017
Peer-review started: March 31, 2017
First decision: April 18, 2017
Revised: June 21, 2017
Accepted: July 7, 2017
Article in press: July 9, 2017
Published online: September 26, 2017


Mesenchymal stromal cells (MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation. MSC activation via specific receptors is a crucial event for these cells to exert their immunosuppressive response. The aryl-hydrocarbon receptor (AhR) is a sensitive molecule for external signals and it is expressed in MSCs and, upon positive activation, may potentially regulate the MSC-associated immunomodulatory function. Consequently, signalling pathways linked to AhR activation can elucidate some of the molecular cascades involved in MSC-mediated immunosuppression. In this minireview, we have noted some important findings concerning MSC regulation via AhR, highlighting that its activation is associated with improvement in migration and immunoregulation, as well as an increase in pro-regenerative potential. Thus, AhR-mediated MSC activation can contribute to new perspectives on MSC-based therapies, particularly those directed at immune-associated disorders.

Key Words: Mesenchymal stromal cells, Aryl-hydrocarbon receptor, Cell activation and immunosuppression

Core tip: The aryl-hydrocarbon receptor (AhR) is an endogenous sensor expressed in mesenchymal stromal cells (MSCs), regulating their immunomodulatory function. Therefore, in this review, we summarize important reports that demonstrate that AhR activation can substantially modulate the function of MSCs by mechanisms associated with: (1) The induction of the death signal in pro-inflammatory cells; (2) the suppression of pro-inflammatory genes/cytokines; (3) the improvement of migration and regenerative potential in acute inflammatory models; (4) the inhibition of mesodermal differentiation; and (5) the up-regulation of global immunosuppression. Thus, the influence of AhR activation on MSC function can establish new perspectives on MSC-based therapies, especially for immune-associated diseases.

Multipotent mesenchymal stromal cells

Multipotent mesenchymal stromal cells (MSCs), also referred to as mesenchymal stem cells, were originally described by Alexander Friedenstein in 1976 as nonhaematopoietic marrow cells in culture[1]. MSCs were identified as stromal cells that present plastic adherent characteristics and the ability to form in vitro fibroblast-like colonies (CFU-F). In 1991, Caplan defined MSCs as a supportive cell population capable of differentiating into several mesodermal cell lineages including muscle, bone marrow stroma, fibroblasts, osteocytes, adipocytes and chondrocytes[2].

Phenotypically, MSCs are characterized by the expression of surface membrane molecules such as endoglin (CD105), NT5E (CD73), and Thy-1 (CD90) and the lack of expression of haematopoietic (CD45, CD34, CD11b/c and CD19) and endothelial (CD31, KDR) markers and of HLA-DR, an immune-associated molecule linked to major histocompatibility complex class II (MHC II)[3]. In addition, MSCs resemble vascular pericytes, and due to their wide perivascular distribution[4,5], these cells can be identified and expanded ex vivo from a multitude of tissues and organs, for instance: (1) Bone marrow[6]; (2) the umbilical cord[6]; and (3) adipose tissue[7], highlighting MSCs as a very attractive cell subpopulation for several clinical applications.

From a therapeutic perspective, MSCs possess advantages such as low immunogenicity, migration to injured tissues and the production of various trophic/growth factors (e.g., cytokines, chemokines and diverse growth factors), which may be related primarily to the mechanisms of immunoregulation, anti-fibrosis, the induction of endogenous tissue progenitor cells, anti-apoptosis, pro-angiogenesis and chemoattraction. Moreover, MSCs may act as effector agents in the modulation of internal gene expression by releasing extracellular microvesicles enriched with small regulatory RNAs[8-10].

In light of their functional multipotentiality, MSCs are essentially distinguished from other cells by retaining immunomodulatory properties that globally reduce the inflammation process, suppressing cellular alloreactivity. In this regard, studies have shown that the infusion of MSCs reduces local and systemic tissue injury in distinct experimental models, e.g., neural encephalomyelitis[11], pulmonary fibrosis[12], kidney injury[13] and heart inflammation[14], mainly via shifting from a pro-inflammatory to an anti-inflammatory profile. Thus, the immunosuppressive abilities of MSCs may be useful to repair tissue damaged by immune system aggression, for instance: (1) Crohn’s disease[15]; (2) ulcerative colitis[16]; (3) graft-versus-host disease (GVHD) followed by halogen transplantation[17]; and (4) organ rejection in transplants[18]. However, the majority of clinical trials with MSCs remain in phase I/II studies, and most have not clearly described a precise therapeutic response[19]. In this context, the complete elucidation of the mechanisms associated with the in vivo therapeutic effects of MSCs remains a target of intense investigation.

To date, scientists have considered MSCs a heterogenous population with several factors that can interfere in their therapeutic efficacy, such as phenotype, proliferation, secretory profile, tissue origin, donor age, culture and expansion method conditions (i.e., growth factors, cell confluence, passages, oxygen pressure and biomaterials)[20,21]. Considering MSCs a manufactured “product” for cell-based therapy, it is essential to standardize operational processes, which must be in accordance with guidelines assigned by the international programme of good manufacturing practices, also known as “GMP”. Thus, given the high heterogeneity of cultured MSCs, it is not surprising that MSC-based therapies have not yet become a reality in operating centers distributed in several countries.

In an attempt to establish a global organizational process for MSC therapeutic programmes, there are potential strategies for refining the preparation and application of MSC cultures. According to several described approaches, the activation of MSCs via specific receptors is an innovative and accessible methodology for standardizing the use of these cell populations. Studies have found that MSCs express certain key receptors (e.g., TLRs, TNFRs, INFRs) that are activated by the inflammatory microenvironment, modulating its immunosuppressive activity[22,23]. This phenomenon was already demonstrated in vitro and in vivo, where important molecules (i.e., TNF-α, INF-γ, PAMPs, DAMPs, IDO, iNOS, PGE-2) and signalling pathways (i.e., PKR, STAT-1, NF-κB) were shown to be regulated during MSCs activation. In fact, one study found that MSCs exposed to IFN-γ became activated and efficiently suppressed the deleterious effects of an in vivo GVHD experimental model almost five-fold more strongly than unstimulated MSCs[24]. However, the precise role of each receptor, its molecular interactions and its impact on the biology of MSCs yet remain to be investigated.


The aryl-hydrocarbon receptor (AhR) is a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors and is characterized as ligand-dependent transcriptional regulator acting on the modulation of a distinct number of genes associated with several biological processes including: (1) The cell cycle; (2) apoptosis; (3) hypoxia; (4) the circadian cycle; (5) differentiation; (6) haematopoiesis; (7) migration; and (8) the immune response[25]. AhR is considered a multifunctional sensor that responds to toxic/pollutant signals from the environment (e.g., dioxins, pollutants and by-products of metabolism), promoting the regulation of gene expression in responsive cells. AhR can be stimulated by a myriad of specific endogenous or exogenous ligands called hydrophobic aromatic hydrocarbons [e.g., polycyclic aromatic hydrocarbons (PAHs), halogenated aromatic hydrocarbons (HAHs) and planar polychlorinated biphenyls (PCBs)], which can be represented by two main classes: (1) Synthetic and non-biological: e.g., dioxins and dibenzofurans; and (2) natural and biological: e.g., carotenoids, flavonoids and tryptophan-derived metabolites, such as kynurenines[26,27].

AhR activation starts when a chemical signal enters the target cells and binds with strong affinity to the AhR cytosolic multiprotein complex, which is associated with actin filaments in the cytoplasm. This complex is composed of two Hsp90 chaperone molecules, along with co-chaperones such as hepatitis B virus X-associated protein (XAP2 or AIP) and p23 protein. After stimulation, AhR changes its conformational structure to present the nuclear localization sequence, which promotes its own translocation from the cytoplasm to the nucleus via the importin β protein. In the nucleus, the AhR-ligand complex detaches from the triplex protein (hsp90/XAP2/p23) to form a dimer with a nuclear protein responsible for AhR translocation, ARNT, which converts AhR to an active isoform with elevated affinity for DNA. Then, the AhR-ligand-ARNT complex binds to a specific promoter regulatory region on DNA [5’-T (N) GCGTG-3’] known as the dioxin-responsive element/sequence (DRE), which is located upstream of the specific CYP1A1 locus or other genes responsive to the AhR signal. In contrast, the dimerization of ARNT with AhR repressor protein (AhRR) leads to non-association of the AhR-ligand complex and ARNT protein, and consequently, the AhR-ligand complex exposes its nuclear export sequence to the cytoplasm and is further conducted to the ubiquitination and proteasome degradation process (Figure 1)[28,29].

Figure 1
Figure 1 Illustration demonstrating a hypothetical summary of the potential effect of aryl-hydrocarbon receptor activation on multipotent mesenchymal stromal cell function. AhR-mediated MSC activation occurs by a cascade of events that substantially modulate the function of the MSCs by mechanisms associated with: (1) The induction of death signalling in pro-inflammatory cells, i.e., pre-B cells; (2) suppression of pro-inflammatory cytokines, i.e., IL-6; (3) the improvement of migration and regenerative potential in acute inflammatory models, i.e., asthma; (4) the inhibition of mesodermal differentiation, i.e., adipogenesis; and (5) the up-regulation of global immunosuppression, i.e., the up-regulation of immunoregulatory genes. AhR: Aryl-hydrocarbon receptor; MSC: Multipotent mesenchymal stromal cell.

AhR is closely linked to the regulation and control of immunity, and there is a substantial amount of evidence supporting the hypothesis that AhR may influence PAH/HAH/PPB-mediated immunoregulation[27,30]. Thus, some reports have shown that AhR activation by particular ligands (i.e., LPS, tetrachlorodibenzo-p-dioxin or TCDD, tryptophan metabolites) can differentially modulate various effects on immunological cells, for example: (1) The function and development of regulatory T cells; (2) the differentiation of Th17 cells; (3) the generation and activity of monocytes and dendritic cells[31-33]; (4) the growth and maturation of mast cells; (5) differentiation/maturation and antibody production by B cells; (6) polarization and cytokine production in macrophages[34,35]; and (7) haematopoietic stem cell expansion, migration, and plasticity[36,37]. Another emerging aspect associated with AhR transcriptional biology involves its cooperative relationship with other signalling pathways, which may interact with AhR or by antagonism, such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), or by synergism, such as the signal transducer and activator of transcription 1 (STAT-1) and the nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2). These multiple interactions of different signalling pathways can generate distinct responses according to the nature of the stimulus and the cell type target and thus qualifies as a tissue-specific molecular interchange[26,29,38].

Functionally, AhR can regulate an extensive number of protein-coding genes, specifically those associated with xenobiotic metabolizing enzymes, such as CYP1A1, which is a member of the superfamily of oxidative enzymes called cytochrome P-450 monooxygenases[28]. Among the potential ligands related to AhR activation, the tryptophan degradation products (i.e., tryptamine and kynurenine) are considered natural endogenous stimuli. Under normal conditions, these metabolites are classified as weak inducers, but after a physiological disturbance, their concentration may rise abruptly, leading to strong activation via CYP1A1 signalling[28]. In this sense, we can assume that an environment of intense inflammation and tissue injury may contain sufficient tryptophan-derived products for MSC activation via AhR, improving the MSC-mediated immunotherapeutic responses. According to these findings, we believe that the immunomodulatory potential of MSCs can be strictly regulated by AhR, and their activation may be essential for MSCs to exert their immunosuppressive response. Indeed, some PAH/HAH-derived metabolites themselves can, either directly or indirectly via AhR, down-regulate immune-associated pathways such as the antigen-specific T and B cell responses, compromising lymphocyte development. However, the influence of AhR on the regulation of MSC-induced immunosuppression remains poorly investigated[30].


To explore the participation of AhR in MSC activation, it was predicted that MSC priming by AhR is a mechanism intimately associated with its immunotherapeutic response. According to this perspective, it has been shown in vitro that MSCs, under standard conditions, support the growth/differentiation of B lymphocytes, but when the MSCs are pre-stimulated by AhR agonist (i.e., DMBA), these cells exert an inverse immunoregulatory response, inducing apoptosis by cell-cell contact in CD43+ pro/pre-B cells. This cell death signal is regulated mainly via a specific soluble stromal cell-dependent death signal that is presumably regulated by its responsive AhR gene, CYP1A1[10,30,39,40]. Later, the authors of the same study reported that the addition of a precise and competitive inhibitor of AhR, α-naphthoflavone (α-NF), blocked DMBA-induced pre-B cell apoptosis in these bone marrow cell co-cultures[39].

Subsequently, another work showed that the activation of AhR in MSCs can also modulate their secretory profile. In this report, the MSCs were stimulated with AhR-specific ligands (i.e., DMBA and TCDD), and after stimulation, these cells had their production of mRNA/protein of interleukin-6 (IL-6) suppressed through a process partially regulated by the coactivation of NF-κB signalling pathways[41]. IL-6 is required for the growth and terminal differentiation of progenitor blood cells, and its aberrant expression is reportedly associated with autoimmune-related disorders (i.e., systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis)[42-44]. Thus, this evidence illustrates the intrinsic importance of AhR-mediated MSC activation, highlighting the role of the IL-6/AhR axis in the regulation of the immune system.

Additionally, it was observed that the therapeutic abilities of MSCs can be modulated by AhR activation. The MSCs were activated by AhR-specific agonists (i.e., TCDD and cockroach allergen extract) and showed increased CYP1A1 and CYP1B1 expression. This process was accompanied by an elevated migration potential in vitro. Later, the authors also demonstrated in mouse models of experimental asthma that MSCs activated by AhR efficiently engrafted to injury sites and attenuated allergen-induced lung inflammation (i.e., reduced cell infiltrate and change cytokine profile), mainly via TGF-β1 modulation[45].

Moreover, it was determined that AhR stimulation in MSCs can also prevent their multipotent differentiation potential. It was shown that treatment with benzo(a)pyrene (BPs), a specific AhR agonist, markedly inhibited the terminal adipogenic differentiation of MSCs in an AhR-dependent manner, with reduced expression of classical adipogenic markers (FABP4), triglyceride enzymes (G3PDH) and adipogenic transcription factors (PPARγ and CEBPβ)[31]. Despite the decreased expression of AhR in differentiated MSCs, the expression of its target gene CYP1B1 remained elevated, indicating that AhR activation was fully functional during adipogenesis. Later, this same study demonstrated that the use of α-NF, an AhR antagonist, abrogated the AhR-mediated inhibition of MSC adipogenesis[31]. Complementarily, another report demonstrated that BP treatment inhibited adipocyte differentiation in vitro by down-regulating the PPARγ signal and increased the expression of cytochrome P450 (CYP1A1) in canine MSCs[46]. In addition, it was detected in vitro that TCDD-stimulated MSCs suppressed the mRNA levels of osteoblastic markers (i.e., Runx2, Ocn and Alp) in a dose-dependent manner through a process mediated by the inhibition of β-catenin expression. Later, similar observations in MSCs derived from inflamed collagen-induced arthritis mice (a possible environment for AhR activation) showed elevated nuclear expression and translocation of AhR and, in consequence, inhibition of osteogenesis-associated genes as well as reduced β-catenin expression[47]. In fact, an additional study verified that AhR activation by BPs inhibited the MSC mesodermal differentiation, and when these activated MSCs were applied in a mouse model of bone fracture, the tibial ossification was affected mainly via SMAD-dependent (e.g., TGF-β1/SMAD4) and SMAD-independent (e.g., TGF-β1/ERK/AKT) signals[48]. Therefore, these results illustrate that the adipogenesis and osteogenesis signalling pathways are also potential targets for AhR regulation in MSCs.

Finally, another group found that the activation of MSCs through kynurenine, a natural AhR agonist, can enhance its immunosuppressive response. The authors detected that MSCs stimulated by kynurenine were more effective in suppressing in vitro lymphocyte proliferation than MSCs stimulated by IFN-γ and TGF-β separately. Further, the analysis of cytokines in the supernatants of lymphocyte/MSC co-cultures demonstrated that the combination of kynurenine with IFN-γ and TGF-β stimuli significantly reduced IL-6 and IL-17 secretion. In line with these findings, the authors also found that the combination of three effector stimuli (IFN-γ, TGF-β and kynurenine) promoted the overexpression of important immunomodulatory genes in MSCs (e.g., iNOS, IDO, COX2, HO-1, PGE-2, LIF and PD-L1). Later, when these triple-activated MSCs were used in the treatment of an experimental model of GVHD, the stimulated MSCs substantially decreased the inflammation and tissue injury score at a more significant level than normal unstimulated MSCs[49].

Altogether, these recent studies suggest that AhR activation can substantially modulate the function of MSCs by mechanisms associated with: (1) The induction of the death signal in pro-inflammatory cells, i.e., pre-B cells; (2) the suppression of pro-inflammatory cytokines, i.e., IL-6; (3) the improvement of migration and regenerative potential in acute inflammatory models, i.e., asthma and GVHD; (4) the inhibition of mesodermal differentiation, i.e., adipogenesis and osteogenesis; and (5) the up-regulation of global immunosuppression, i.e., the up-regulation of immunoregulatory genes (Figure 1).


The immunosuppressive properties of MSCs are of great interest for cellular therapy; however, randomized double-blind clinical studies have not shown clear benefits to date[42,50]. This inconclusive large-scale clinical result may be associated with the variety of cytokines/agonists in the distinct environments that MSCs encounter in vivo. In this context, the molecular mechanisms involved in the reparative status of MSCs through the activation of sensitive immune-associated receptors are so far unclarified, and, therefore, they are indispensable parameters for investigation. Thus, MSC activation is currently considered a sine qua non condition for MSCs and their bioproducts (i.e., trophic factors and microvesicles) to exert their immunoregulatory response.

Considering this perspective, the quality of the immunoregulatory profile of MSCs can be considerably improved when these cells are exposed to sufficient levels of sensitive ligands (i.e., cytokines/growth factors). On the other hand, MSCs not subjected to pre-stimulation tend to decrease or lose their intrinsic immunosuppressive potential, promoting an undesired inflammatory response[49]. In this context, we hypothesized that the optimal immunomodulatory potential of MSCs can be obtained by establishing a steady regulatory phenotype in MSCs using precise MSC-responsive ligands as AhR agonists. Thus, the activation of AhR in MSCs should be extensively explored as a mechanism in relevant pre-clinical and experimental studies, in the attempt to improve the applicability of MSCs in a set of degenerative and immunological diseases.

However, questions regarding the mechanisms of the MSC immunoregulatory response remain inconclusive. In this sense, MSC immunoregulation can vary among species, for instance, IDO up-regulation in MSCs is better described in humans, while inducible nitric oxide synthase (iNOS) is a key regulatory enzyme in mouse MSC immunomodulation[49]. In addition, the elucidation of the cross-talk between AhR agonists and other sensitive molecules (e.g., IFNγ, TGF-β, TNF-α, LPS and others) is a detrimental factor in applying the immunosuppressive response of MSCs. Moreover, the influence of MSCs in another set of experimental models is also important to consider. In line with this purpose, Aleman et al[49] (2015) reported that kynurenine, in combination with other effector stimuli (IFNγ and TGF-β), can induce elevated IDO, COX2, iNOS, and PGE-2 expression in MSCs and, at the same time, reduce the expression of EGFR, MHC II and IL-6. Thus, further investigations should focus on identifying the major components that trigger the activation of the AhR signal and its cross-talk with other signalling pathways, to precisely understand the regulatory mechanism of AhR influence on MSC function. In line with this goal, aspects of this mechanism have begun to be investigated, such as the impact of AhR activation on MSC adipogenesis or osteogenesis; nevertheless, the specific AhR-dependent signalling pathways by which AhR agonists affect MSC-associated mesodermal differentiation also remain to be determined.

In conclusion, we hope that the findings discussed here in this minireview will contribute to better comprehension of the major mechanisms behind MSC immunoregulation and provide a basic background for the development of innovative studies focused on the molecular cascade associated with AhR activation in MSCs. In summary, the study of AhR activation can promote new insights for the better investigation of molecular signalling pathways associated with the regenerative and immunosuppressive potential of MSCs, and consequently, these studies will support the development of potential MSC-derived therapies for a wide variety of immune-associated disorders.


We would like to thank all the professionals who contributed to the discussion and elaboration of this minireview.


Manuscript source: Invited manuscript

Specialty type: Cell and tissue engineering

Country of origin: Brazil

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P- Reviewer: Liu L, Liu SH, Miyagoe-Suzuki Y, Saeki K S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ

1.  Shi L, Zhang Z, Fang S, Xu J, Liu J, Shen J, Fang F, Luo L, Yin Z. Heat shock protein 90 (Hsp90) regulates the stability of transforming growth factor beta-activated kinase 1 (TAK1) in interleukin-1beta-induced cell signaling. Mol Immunol. 2009;46:541-550.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 17]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
2.  Yang K, Shi H, Qi R, Sun S, Tang Y, Zhang B, Wang C. Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells. Mol Biol Cell. 2006;17:1461-1471.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 72]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
3.  Yun TJ, Harning EK, Giza K, Rabah D, Li P, Arndt JW, Luchetti D, Biamonte MA, Shi J, Lundgren K. EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity. J Immunol. 2011;186:563-575.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 73]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
4.  D'Avila H, Roque NR, Cardoso RM, Castro-Faria-Neto HC, Melo RC, Bozza PT. Neutrophils recruited to the site of Mycobacterium bovis BCG infection undergo apoptosis and modulate lipid body biogenesis and prostaglandin E production by macrophages. Cell Microbiol. 2008;10:2589-2604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 74]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
5.  Petrofsky M, Bermudez LE. Neutrophils from Mycobacterium avium-infected mice produce TNF-alpha, IL-12, and IL-1 beta and have a putative role in early host response. Clin Immunol. 1999;91:354-358.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 68]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
6.  Sawant KV, Cho H, Lyons M, Ly LH, McMurray DN. Guinea pig neutrophil-macrophage interactions during infection with Mycobacterium tuberculosis. Microbes Infect. 2010;12:828-837.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 15]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
7.  Hage CA, abdul-Mohammed K, Antony VB. Pathogenesis of pleural infection. Respirology. 2004;9:12-15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 20]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
8.  O'Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP. The immune response in tuberculosis. Annu Rev Immunol. 2013;31:475-527.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 842]  [Cited by in F6Publishing: 874]  [Article Influence: 87.4]  [Reference Citation Analysis (0)]
9.  Gertsch J. Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action? Commun Integr Biol. 2008;1:26-28.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M, Mach F, Steffens S. CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol. 2009;46:612-620.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 121]  [Cited by in F6Publishing: 130]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
11.  Kang DD, Lin Y, Moreno JR, Randall TD, Khader SA. Profiling early lung immune responses in the mouse model of tuberculosis. PLoS One. 2011;6:e16161.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 92]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
12.  Keller C, Hoffmann R, Lang R, Brandau S, Hermann C, Ehlers S. Genetically determined susceptibility to tuberculosis in mice causally involves accelerated and enhanced recruitment of granulocytes. Infect Immun. 2006;74:4295-4309.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 123]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
13.  Murikinati S, Jüttler E, Keinert T, Ridder DA, Muhammad S, Waibler Z, Ledent C, Zimmer A, Kalinke U, Schwaninger M. Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment. FASEB J. 2010;24:788-798.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 119]  [Cited by in F6Publishing: 130]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
14.  Gopal R, Monin L, Torres D, Slight S, Mehra S, McKenna KC, Fallert Junecko BA, Reinhart TA, Kolls J, Báez-Saldaña R. S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Respir Crit Care Med. 2013;188:1137-1146.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 151]  [Article Influence: 15.1]  [Reference Citation Analysis (0)]
15.  Singh UP, Singh NP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol. 2012;258:256-267.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 78]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
16.  Toguri JT, Lehmann C, Laprairie RB, Szczesniak AM, Zhou J, Denovan-Wright EM, Kelly ME. Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis. Br J Pharmacol. 2014;171:1448-1461.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 60]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
17.  Fukuda S, Kohsaka H, Takayasu A, Yokoyama W, Miyabe C, Miyabe Y, Harigai M, Miyasaka N, Nanki T. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskelet Disord. 2014;15:275.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 65]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
18.  Smith SR, Denhardt G, Terminelli C. The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models. Eur J Pharmacol. 2001;432:107-119.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Byrne ST, Denkin SM, Zhang Y. Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis. J Antimicrob Chemother. 2007;59:313-316.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 80]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
20.  Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61-65.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3564]  [Cited by in F6Publishing: 3705]  [Article Influence: 123.5]  [Reference Citation Analysis (0)]
21.  Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161-202.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561-564.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3592]  [Cited by in F6Publishing: 3761]  [Article Influence: 114.0]  [Reference Citation Analysis (0)]
23.  Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232:54-61.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  McHugh D, Tanner C, Mechoulam R, Pertwee RG, Ross RA. Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Mol Pharmacol. 2008;73:441-450.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 103]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
25.  Montecucco F, Burger F, Mach F, Steffens S. CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol. 2008;294:H1145-H1155.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 114]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
26.  Lowe DM, Redford PS, Wilkinson RJ, O’Garra A, Martineau AR. Neutrophils in tuberculosis: friend or foe? Trends Immunol. 2012;33:14-25.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 216]  [Cited by in F6Publishing: 229]  [Article Influence: 19.1]  [Reference Citation Analysis (0)]
27.  Rom S, Zuluaga-Ramirez V, Dykstra H, Reichenbach NL, Pacher P, Persidsky Y. Selective activation of cannabinoid receptor 2 in leukocytes suppresses their engagement of the brain endothelium and protects the blood-brain barrier. Am J Pathol. 2013;183:1548-1558.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 46]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
28.  Ramirez SH, Haskó J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M. Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci. 2012;32:4004-4016.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 168]  [Cited by in F6Publishing: 176]  [Article Influence: 16.0]  [Reference Citation Analysis (0)]
29.  Heit B, Robbins SM, Downey CM, Guan Z, Colarusso P, Miller BJ, Jirik FR, Kubes P. PTEN functions to ‘prioritize’ chemotactic cues and prevent ‘distraction’ in migrating neutrophils. Nat Immunol. 2008;9:743-752.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 200]  [Cited by in F6Publishing: 206]  [Article Influence: 13.7]  [Reference Citation Analysis (0)]
30.  Dorhoi A, Kaufmann SH. Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis. Semin Immunopathol. 2016;38:153-166.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 78]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
31.  Astani A, Reichling J, Schnitzler P. Screening for antiviral activities of isolated compounds from essential oils. Evid Based Complement Alternat Med. 2011;2011:253643.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 131]  [Cited by in F6Publishing: 146]  [Article Influence: 12.2]  [Reference Citation Analysis (0)]
32.  Basha RH, Sankaranarayanan C. β-Caryophyllene, a natural sesquiterpene lactone attenuates hyperglycemia mediated oxidative and inflammatory stress in experimental diabetic rats. Chem Biol Interact. 2016;245:50-58.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 81]  [Article Influence: 10.1]  [Reference Citation Analysis (0)]
33.  Hammami S, Jmii H, El Mokni R, Khmiri A, Faidi K, Dhaouadi H, El Aouni MH, Aouni M, Joshi RK. Essential Oil Composition, Antioxidant, Cytotoxic and Antiviral Activities of Teucrium pseudochamaepitys Growing Spontaneously in Tunisia. Molecules. 2015;20:20426-20433.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 37]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
34.  Asdadi A, Hamdouch A, Oukacha A, Moutaj R, Gharby S, Harhar H, El Hadek M, Chebli B, Idrissi Hassani LM. Study on chemical analysis, antioxidant and in vitro antifungal activities of essential oil from wild Vitex agnus-castus L. seeds growing in area of Argan Tree of Morocco against clinical strains of Candida responsible for nosocomial infections. J Mycol Med. 2015;25:e118-e127.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 21]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
35.  Antony VB, Sahn SA, Antony AC, Repine JE. Bacillus Calmette-Guérin-stimulated neutrophils release chemotaxins for monocytes in rabbit pleural spaces and in vitro. J Clin Invest. 1985;76:1514-1521.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 72]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
36.  Kasahara K, Sato I, Ogura K, Takeuchi H, Kobayashi K, Adachi M. Expression of chemokines and induction of rapid cell death in human blood neutrophils by Mycobacterium tuberculosis. J Infect Dis. 1998;178:127-137.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Costa MF, de Souza-Martins R, de Souza MC, Benjamim CF, Piva B, Diaz BL, Peters-Golden M, Henriques Md, Canetti C, Penido C. Leukotriene B4 mediates gammadelta T lymphocyte migration in response to diverse stimuli. J Leukoc Biol. 2010;87:323-332.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 32]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
38.  Eruslanov EB, Lyadova IV, Kondratieva TK, Majorov KB, Scheglov IV, Orlova MO, Apt AS. Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect Immun. 2005;73:1744-1753.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 207]  [Cited by in F6Publishing: 215]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
39.  Dorhoi A, Kaufmann SH. Versatile myeloid cell subsets contribute to tuberculosis-associated inflammation. Eur J Immunol. 2015;45:2191-2202.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 55]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
40.  Legault J, Pichette A. Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol. 2007;59:1643-1647.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 262]  [Cited by in F6Publishing: 264]  [Article Influence: 17.6]  [Reference Citation Analysis (0)]
41.  Rodrigues-Bastos AP, Nascimento CX, Werneck-Barroso E, Cordeiro RS, Henriques Md, Moura AC. Comparison between C57Bl/6 and C57Bl/10 mycobacterial mouse pleurisy with respect to cellular migration and nitric oxide production. Inflammopharmacology. 2004;12:353-372.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Niggli V. Signaling to migration in neutrophils: importance of localized pathways. Int J Biochem Cell Biol. 2003;35:1619-1638.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Gui H, Liu X, Liu LR, Su DF, Dai SM. Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis. Immunobiology. 2015;220:817-822.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 41]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
44.  Loizzo MR, Tundis R, Menichini F, Saab AM, Statti GA, Menichini F. Antiproliferative effects of essential oils and their major constituents in human renal adenocarcinoma and amelanotic melanoma cells. Cell Prolif. 2008;41:1002-1012.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 99]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
45.  Werneck-Barroso E, Moura AC, Monteiro MM, Menezes de Lima Júnior O, de Meirelles MN, Henriques MG. Distinct ability to accumulate eosinophils during the inflammatory cellular response to M. bovis BCG in the mouse pleural cavity. Inflamm Res. 2000;49:206-213.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Galdino PM, Nascimento MV, Florentino IF, Lino RC, Fajemiroye JO, Chaibub BA, de Paula JR, de Lima TC, Costa EA. The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:276-284.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 82]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
47.  Ghelardini C, Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A. Local anaesthetic activity of beta-caryophyllene. Farmaco. 2001;56:387-389.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Paula-Freire LI, Andersen ML, Gama VS, Molska GR, Carlini EL. The oral administration of trans-caryophyllene attenuates acute and chronic pain in mice. Phytomedicine. 2014;21:356-362.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 54]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
49.  Aleman M, de la Barrera SS, Schierloh PL, Alves L, Yokobori N, Baldini M, Abbate E, Sasiain MC. In tuberculous pleural effusions, activated neutrophils undergo apoptosis and acquire a dendritic cell-like phenotype. J Infect Dis. 2005;192:399-409.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 32]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
50.  Afonso PV, Janka-Junttila M, Lee YJ, McCann CP, Oliver CM, Aamer KA, Losert W, Cicerone MT, Parent CA. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev Cell. 2012;22:1079-1091.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 217]  [Cited by in F6Publishing: 198]  [Article Influence: 18.0]  [Reference Citation Analysis (0)]