Despite decades of research, impaired extremity wound healing in type 2 diabetes remains a significant driver of patient morbidity, mortality, and health care costs. Advances in surgical and medical therapies, including the advent of endovascular interventions for peripheral artery disease and topical therapies developed to promote wound healing, have not reduced the frequency of lower leg amputations for nonhealing wounds in type 2 diabetes. This brief report is aimed at reviewing the roles of various cell types in tissue repair and summarizing the known dysfunctions of these cell types in diabetic foot ulcers. Recent advances in our understanding of the epigenetic regulation in immune cells identified to be altered in type 2 diabetes are summarized, and particular attention is paid to the developing research defining the epigenetic regulation of structural cells, including keratinocytes, fibroblasts, and endothelial cells. Gaps in knowledge are highlighted, and potential future directions are suggested based on the current state of the field.

Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications-including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities-and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.

Insulin resistance (IR) is a key factor in the development of type 2 diabetes, and M2-like macrophages are important in maintaining normal glucose homeostasis. Our previous research has demonstrated that the total saponins from Panax japonicus (TSPJ) reduce IR in adipocytes and promote the M2 polarization of macrophages, but the molecular mechanism is unclear.

In the study, we aimed to elucidate whether TSPJ mitigate IR by enhancing the intercellular communication between adipocytes and macrophages and describe how the exosomes from bone marrow-derived macrophages (BMDMs) modulate the insulin sensitivity of adipocytes via miR204.

We used both in vitro and in vivo models to study the effects of TSPJ on IR, with a particular emphasis on the exosomes from M2-type BMDMs. Furthermore, we investigated the mechanisms by which exosomal miR204 and its downstream target Elovl6 influence IR in an obese mouse model, as well as in adipocytes with double inhibition of miR204 and Elovl6.

In the animal model, TSPJ significantly increased miR204 expression in BMDMs-derived exosomes and decreased the level of Elovl6 in adipocytes. However, when the C75BL/6 mice had miR204 ablation, TSPJ became less capable of enhancing insulin sensitivity, and the expressions of Irs1, Insr, and Slc2a4 in the adipose tissue decreased. In the cell model where the macrophages carried miR204 ablation and the adipocytes had Elovl6 knockdown, the expressions of IR-related genes increased in the adipocytes.

TSPJ mitigated IR through adipocyte-BMDM crosstalk mediated by exosomes via the miR204/Elovl6 pathway.

White adipose tissue (WAT) is highly flexible and was previously considered a passive location for energy storage. Its endocrine function has been established for several years, earning it the title of an "endocrine organ" due to its ability to secrete many adipokines that regulate metabolism. WAT is one of the core tissues that influence insulin sensitivity. Its dysfunction enhances insulin resistance and type 2 diabetes (T2D) progression. However, T2D may cause WAT dysfunction, including changes in distribution, metabolism, adipocyte hypertrophy, inflammation, aging, and adipokines and free fatty acid levels, which may exacerbate insulin resistance. This review used PubMed to search WAT dysfunction in T2D and the effects of these changes on insulin resistance. Additionally, we described and discussed the effects of antidiabetic drugs, including insulin therapy, sulfonylureas, metformin, glucose-like peptide-1 receptor agonists, thiazolidinediones, and sodium-dependent glucose transporters-2 inhibitors, on WAT parameters under T2D conditions.

Eosinophils are traditionally known for their role in immune defense against parasites and their involvement in various immunopathologies, including eosinophilic airway diseases, eosinophilic dermatoses, and gastrointestinal disorders. However, recent findings from our group and other leading laboratories have broadened this perspective, revealing that eosinophils also play crucial roles in tissue development, homeostasis, and regeneration. This review aims to highlight the regulatory functions of eosinophils within the bone niche and emphasize the importance of further research into their role in bone biology.

Growing evidence suggests that eosinophils are key regulators of bone metabolism, extending beyond their established roles in immunity and inflammation. They contribute to bone homeostasis by inhibiting osteoclast differentiation, helping to prevent excessive bone resorption in osteoporosis and inflammatory arthritis. Additionally, eosinophils may promote osteoblast-mediated bone formation, modulate the mesenchymal and hematopoietic stem cell niche, and contribute to the bone microenvironment by affecting vascularization and extracellular matrix composition. However, their impact may vary under pathological conditions. Patients with eosinophilic disorders are often at an increased risk of osteoporosis and fragility fractures, though this is largely attributed to disease-related treatments rather than eosinophil activity itself. Despite emerging insights into the role of eosinophils in bone biology, the underlying mechanisms remain incompletely understood. Further research is essential to elucidate how eosinophils influence bone physiology and pathology.

Colorectal cancer (CRC) is the third most common cancer worldwide and has one of the highest mortality rates. Considering its nonlinear etiology, many risk factors are associated with CRC formation and development, with obesity at the forefront. Obesity is regarded as one of the key environmental risk determinants for the pathogenesis of CRC. Excessive food intake and a sedentary lifestyle, together with genetic predispositions, lead to the overgrowth of adipose tissue along with a disruption in the number and function of its building cells. Adipose tissue-resident cells may constitute part of the CRC microenvironment. Alterations in their physiology and secretory profiles observed in obesity may further contribute to CRC progression, and despite similar localization, their contributions are not equivalent. They can interact with CRC cells, either directly or indirectly, influencing various processes that contribute to tumorigenesis. The main aim of this review is to provide insights into the diversity of adipose tissue resident cells, namely, adipocytes, adipose stromal cells, and immunological cells, regarding the role of particular cell types in co-forming the CRC microenvironment. The scope of this study was also devoted to the abnormalities in adipose tissue physiology observed in obesity states and their impact on CRC development.

Parasites generally survive in their hosts by employing various immunomodulation and immune evasion mechanisms. "helminth therapy" is one strategy that harnesses these parasite-specific beneficial properties for the therapeutic treatment of autoimmune and allergic diseases. Although numerous experimental reports have documented the anti-autoimmune activities of parasitic infections and parasite-derived products, the underlying mechanisms remain insufficiently elucidated due to the significant diversity among parasite species and autoimmune conditions. Rheumatoid arthritis (RA) is one of the most prevalent autoimmune disorders, presenting a substantial opportunity for the therapeutic use of parasites as novel disease-modifying antirheumatic drugs (DMARDs). In this paper, we summarize the immunomodulatory properties of parasites, focusing on their anti-arthritic mechanisms, and discuss the potential of parasite-derived products for the treatment of RA.

Regulatory T cells (Tregs) mediate tissue homeostasis and repair. The function of the interleukin-7 receptor α (IL-7Rα) in nonlymphoid tissue Tregs is still unknown, although low expression of IL-7Rα is a widely accepted marker for Tregs. Here, we show that IL-33R (ST2)-expressing Tregs in the visceral adipose tissue (VAT) express the IL-7Rα at high levels. Treg-specific IL-7Rα-deficient mice exhibited reduced adipose ST2+ Tregs and impaired glucose tolerance, whereas IL-7Rα was dispensable for Tregs in lymphoid tissues. Mice deficient in thymic stromal lymphopoietin (TSLP), an additional ligand for IL-7Rα, displayed a modest decrease in adipose ST2+ Tregs and a reduced accumulation of adipose eosinophils, accompanied by slightly impaired glucose tolerance. In the VAT, mesothelial cells expressed IL-7, whereas adipose stem cells and folate receptor β-expressing tissue-resident macrophages expressed TSLP. Thus, this study indicates the significance of IL-7Rα signaling in the maintenance of VAT Tregs and glucose homeostasis, revealing a novel role for IL-7 and TSLP in immunometabolism.

Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing prediabetes or type 2 diabetes later in life. Recent studies have highlighted the regulation and function of innate lymphoid cells (ILCs) in metabolic homeostasis. However, the multifactorial impact of both overweight/obesity and GDM on the immunological profile of circulating ILCs and the progression to prediabetes are not yet fully elucidated.

Blood samples from 42 women with a history of insulin-treated GDM (GDMi), 33 women with a history of GDM without insulin treatment during pregnancy (GDM), and 45 women after a normoglycemic pregnancy (Ctrl) participating in the ongoing observational PPSDiab study were analyzed by flow cytometry for markers of ILC subsets at the baseline visit (3-16 months postpartum; Visit 1) and 5 years postpartum (58-66 months postpartum; Visit 2).

During the first 5 years postpartum, 18 women of the GDMi group (42.8%), 10 women of the GDM group (30.3%), and 8 participants of the Ctrl group (17.8%) developed prediabetes, respectively. Total circulating type 1 innate lymphoid cells (ILC1s) and NK cell numbers as well as percent HLA-DR+ ILC1s were increased in GDMi versus GDM and Ctrl women both at the baseline visit and the 5-year follow-up. Although ILC subsets at Visit 1 could not predict the progression from GDM to prediabetes, ILC2 frequency was associated with insulin sensitivity index (ISI), whereas percent HLA-DR+ ILC1s were inversely correlated. Moreover, circulating leukocytes and total NK cells were associated with waist circumference and fat mass both at Visit 1 and Visit 2.

Our findings introduce human ILCs as a potential therapeutic target deserving further exploration.

Study ID 300-11.

Eosinophils are essential innate immune cells in allergic responses. Accumulating evidence indicates that eosinophils also participate in the pathogenesis of cardiovascular diseases (CVDs). In clinical studies, high blood eosinophil counts and eosinophil cationic protein levels have been associated with an increased risk of CVD, including myocardial infarction (MI), cardiac hypertrophy, atrial fibrillation, abdominal aortic aneurysm (AAA) and atherosclerosis. However, low blood eosinophil counts have also been reported to be a risk factor for MI, heart failure, aortic dissection, AAA, deep vein thrombosis, pulmonary embolism and ischaemic stroke. Although these conflicting clinical observations remain unexplained, CVD status, timing of eosinophil data collection, and tissue eosinophil phenotypic and functional heterogeneities might account for these discrepancies. Preclinical studies suggest that eosinophils have protective actions in MI, cardiac hypertrophy, heart failure and AAA. By contrast, cationic proteins and platelet-activating factor from eosinophils have been shown to promote vascular smooth muscle cell proliferation, vascular calcification, thrombomodulin inactivation and platelet activation and aggregation, thereby exacerbating atherosclerosis, atrial fibrillation, thrombosis and associated complications. Therefore, eosinophils seem to promote calcification and thrombosis in chronic CVD but are protective in acute cardiovascular settings. In this Review, we summarize the available clinical and preclinical data on the different roles of eosinophils in CVD.

Eosinophils are immune cells that are crucial for the pathogenesis of allergic diseases, such as asthma. These cells play multifunctional roles in various situations, including infection. They are activated during viral infections and exert antiviral activity. Pattern recognition receptors, toll-like receptor 7 and retinoic acid inducible gene-I, are important for the recognition and capture of RNA viruses. In addition, intracellular granule proteins (eosinophil cationic protein and eosinophil-derived neurotoxin) and intracellular nitric oxide production inactivate and/or degrade RNA viruses. Interestingly, eosinophil-synthesizing specialized pro-resolving mediators possess antiviral properties that inhibit viral replication. Thus, eosinophils may play a protective role during respiratory virus infections. Notably, antiviral activities are impaired in patients with asthma, and eosinophil activities are perturbed in proportion with the severity of asthma. The exact roles of eosinophils in RNA virus (rhinovirus, respiratory syncytial virus, and influenza virus)-induced type 2 inflammation-based asthma exacerbation remain unclear. Our research demonstrates that interferons (IFN-α and IFN-γ) stimulate human eosinophils to upregulate antiviral molecules, including guanylate-binding proteins and tripartite motifs. Furthermore, IFN-γ specifically increases the expression of IL5RA, ICAM-1, and FCGR1A, potentially enhancing cellular responsiveness to IL-5, ICAM-1-mediated adhesion to rhinoviruses, and IgG-induced inflammatory responses, respectively. In this review, we have summarized the relationship between viral infections and asthma and the mechanisms underlying the development of antiviral functions of human and mouse eosinophils in vivo and in vitro.

The transition from metabolically healthy obesity to the development of obesity-associated metabolic syndrome and cardiovascular disease is thought to be triggered by a loss in the functional integrity of adipose tissue. Although mature adipocytes are the primary functional units that carry out lipid partitioning in adipose tissue for the promotion of whole-body energy balance, they are supported by a heterogenous collection of nonadipocytes in the stroma. Research over the past couple of decades has expanded perspectives on the homeostatic and pathological roles of the nonadipocyte compartment. Adipose progenitors originate in the embryonic period and drive the developmental adipogenesis that establishes the set point of adiposity. A population of adipocyte progenitors reside in adult depots and serve an important homeostatic role as a reservoir to support adipocyte turnover. Adipocyte hypertrophy in obesity increases the rate of adipocyte death and the ability of progenitors to support this high rate of adipocyte turnover is important for the preservation of the lipid-buffering function of adipose tissue. Some evidence exists to suggest that impaired adipogenesis or a decline in progenitors capable of differentiation is a key event in the development of adipose dysfunction. The efficiency of macrophages to clear the debris and toxic lipids released from dead adipocytes lies at the fulcrum between preservation of adipose function and the progression toward chronic inflammation. Although macrophages in collaboration with other immune cells propagate the inflammation that underlies adipose dysfunction, there is now a greater appreciation for the diverse and unique roles of immune cells within adipose tissue.

Acute lung injury (ALI) is a severe inflammatory condition characterized by dysregulated immune responses and high mortality rates, with limited effective therapeutic options currently available. Panax notoginseng saponins (PNS), bioactive compounds derived from Panax notoginseng, have shown promise in mitigating lipopolysaccharide (LPS)-induced ALI. However, the molecular mechanisms underlying their therapeutic effects remain poorly understood. Given the critical role of M2-like macrophage polarization in resolving inflammation and promoting tissue repair, we investigated whether PNS exerts its protective effects in ALI by modulating this process. Furthermore, we explored the specific involvement of the signal transducer and activator of transcription 6 (STAT6) pathway in mediating these effects.

Chemical profiling of PNS was performed using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), followed by quantitative analysis of its major bioactive components via high-performance liquid chromatography (HPLC). To evaluate the therapeutic efficacy of PNS and its principal constituents, we established an ALI mouse model through intratracheal administration of LPS. Comprehensive assessments included lung field shadowing, oxygen saturation levels, pulmonary function, and systematic histopathological examination. The regulatory effects of PNS on macrophage polarization were examined in THP-1 cells and bone marrow-derived macrophages (BMDMs), with cellular phenotypes analyzed by flow cytometry. To elucidate the mechanistic role of STAT6 in PNS-mediated protection, experiments were conducted using Stat6-deficient BMDMs and Stat6 knockout mice.

UPLC-Q-TOF-MS and HPLC identified and quantified the principal components of PNS: Notoginsenoside R1, Ginsenoside Rg1, Ginsenoside Re, and Ginsenoside Rb1. PNS treatment dose-dependently reduced inflammatory responses in LPS-induced ALI mice, as evidenced by decreased cytokine levels. Each of the four major PNS components independently alleviated ALI symptoms in mice. Pathway analysis revealed 56 potential ALI-related targets, with Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment suggesting that PNS exerts its protective effects by modulating inflammatory signaling pathways. In vitro studies demonstrated that PNS promoted STAT6 phosphorylation and nuclear translocation, enhancing M2-like macrophage polarization and interleukin-10 (IL-10) secretion in a STAT6-dependent manner. Genetic ablation of Stat6 partially reversed the protective effects of PNS on ALI, macrophage polarization, and IL-10 production, confirming the pivotal role of STAT6 in mediating PNS activity.

This study demonstrates that PNS alleviates LPS-induced ALI by promoting STAT6-dependent M2-like macrophage polarization, highlighting its potential as a therapeutic agent for ALI. These findings provide mechanistic insights into the anti-inflammatory actions of PNS and underscore the importance of STAT6 signaling in its protective effects.

Obesity is an exceedingly prevalent and frequent health issue in today's society. Fat deposition is accompanied by low-grade inflammation in fat tissue and throughout the body, leading to metabolic disorders that ultimately promote the onset of obesity-related diseases. The development of obesity is accompanied by cell death events such as apoptosis as well as pyroptosis, however, the role of necroptosis in obesity has been widely reported in recent years. Necroptosis, a mode of cell death distinct from apoptosis and necrosis, is associated with developing many inflammatory conditions and their associated diseases. It also exhibits modulation of apoptosis and pyroptosis. It is morphologically similar to necroptosis, characterized by the inhibition of caspase-8, the formation of membrane pores, and the subsequent rupture of the plasma membrane. This paper focuses on the key pathways and molecules of necroptosis, exploring its connections with apoptosis and pyroptosis, and its implications in obesity. This paper posits that the modulation of necroptosis-related targets may represent a novel potential therapeutic avenue for the prevention and treatment of obesity-induced systemic inflammatory responses, and provides a synopsis of potential molecular targets that may prove beneficial in obesity-associated inflammatory diseases.

Conventional dendritic cells (cDCs) are sentinels of the mammalian immune system that sense a wide range of danger and homeostatic signals to induce appropriately targeted T cell immune responses. Traditionally classified into two main subsets, cDC1 and cDC2, recent research shows that cDC2s exhibit significant heterogeneity and can be further subdivided. Studies in mice and humans show that, beyond their ontogeny, cDC2s acquire dynamic and tissue-specific characteristics that are influenced by local environmental signals, which impact on their functions during homeostasis, inflammation, and infection. The novel concept is proposed that tissue-derived signals and tissue plasticity can override preestablished developmental programming, thereby redefining developmental trajectories and cDC2 functionality. Ultimately, understanding cDC2 heterogeneity and plasticity has important implications for modulating T cell immunity in health and disease.

Macrophages play crucial roles in immune response and tissue homeostasis, with their functions becoming increasingly complex in obesity-mediated metabolic disorders. This review explores the extensive range of macrophage activities within adipose and liver tissues, emphasizing their contribution to the pathogenesis and progression of obesity and its related metabolic dysfunction-associated steatotic liver disease (MASLD). In the context of obesity, macrophages respond adaptively to lipid overloads and inflammatory cues in adipose tissue, profoundly influencing insulin resistance and metabolic homeostasis. Concurrently, their role in the liver extends to moderating inflammation and orchestrating fibrotic responses, integral to the development of MASLD. Highlighting the spectrum of macrophage phenotypes across these metabolic landscapes, we summarize their diverse roles in linking inflammatory processes with metabolic functions. This review advocates for a deeper understanding of macrophage subsets in metabolic tissues, proposing targeted research to harness their therapeutic potential in mitigating MASLD and other metabolic disorders.

Eosinophils are polymorphonuclear cells that have progressively gained attention due to their involvement in multiple diseases and, more recently, in various homeostatic processes. Their well-known roles range from asthma and parasitic infections to less prevalent diseases such as eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, and hypereosinophilic syndrome. In recent years, various biological therapies targeting these cells have been developed, altering the course of eosinophilic pathologies. Recent research has demonstrated differences in eosinophil subtypes and their functions. The presence of distinct classes of eosinophils has led to the theory of resident eosinophils (rEos) and inflammatory eosinophils (iEos). Subtype differences are determined by the pattern of protein expression on the cell membrane and the localization of eosinophils. Most of this research has been conducted in murine models, but several studies confirm these findings in peripheral blood and tissue. The objective of this review is to provide a comprehensive analysis of eosinophils, by recent findings that divide this cell line into two distinct populations with different functions and purposes.

Interleukin-33 (IL-33) is a pleiotropic cytokine of the IL-1 family that plays a key role in innate and adaptive immune responses and contributes to tissue homeostasis. Its role in adipose tissue function has been extensively studied, as adipose tissue serves as an important mediator of metabolic dysfunction. In adipose tissue, IL-33 is primarily produced by stromal cells. Its production is regulated by factors, such as androgens, aging, sympathetic innervation, and various inflammatory stimuli that affect the proliferation and differentiation of IL-33-producing stromal cells. Many studies have elucidated the mechanisms by which IL-33 interacts with the immune system components, local nerve fibers, and adipocytes to influence energy balance, with important consequences in obesity, cold-induced thermogenesis, and aging-related metabolic dysfunction. Here, we detail our current understanding of the molecular events that regulate the production of IL-33 within adipose tissue and discuss its role in regulating adipose function.

Dysregulated lipid metabolism in obesity leads to adipose tissue expansion, a major contributor to metabolic dysfunction and chronic disease. Lipid metabolism and fatty acid changes play vital roles in the progression of obesity. In this proof-of-concept study, Raman techniques combined with histochemical imaging methods were utilized to analyze the impact of a high-fat diet (HFD) on different types of adipose tissue in mice, using a small sample size (n = 3 per group). After six weeks of high-fat diet (HFD) feeding, our findings showed hypertrophy, elevated collagen levels, and increased macrophage presence in the adipose tissues of the HFD group compared to the low-fat diet (LFD) group. Statistical analysis of Raman spectra revealed significantly lower unsaturated lipid levels and higher lipid to protein content in different fat pads (brown adipose tissue (BAT), subcutaneous white adipose tissue (SWAT), and visceral white adipose tissue (VWAT)) with HFD. Raman images of adipose tissues were analyzed using Empty modeling and DCLS methods to spatially profile unsaturated and saturated lipid species in the tissues. It revealed elevated levels of ω-3, ω-6, cholesterol, and triacylglycerols in BAT adipose tissues of HFD compared to LFD tissues. These findings indicated that while cholesterol, ω-6/ω-3 ratio, and triacylglycerol levels have risen in the SWAT and VWAT adipose tissues of the HFD group, the levels of ω-3 and ω-6 have decreased following the HFD. The study showed that Raman spectroscopy provided invaluable information at the molecular level for investigating lipid species remodeling and spatial mapping of adipose tissues during HFD.

Although benefits of selection for host resistance to gastro-intestinal nematodes have long been recognized, its costs on production traits remain unclear. A main difficulty when studying those costs is to disentangle genetic effects due to selection from plastic responses induced by infection. Putative costs of host resistance have been extensively investigated in growing sheep. However, while most of those studies have relied on live weight to assess body growth, more comprehensive assessments accounting for body composition are advocated to detect trade-offs. In this study we used 90 female lambs from lines divergently selected on resistance to Haemonchus contortus that we experimentally infected (n = 60) or not (n = 30) under controlled conditions. As those conditions were defined to enable uninfected lambs to fully express their growth potential, we sought to precisely identify the effects of selection for host resistance on health traits and on growth traits. We assessed muscular and fat growth based on repeated measurements with dorsal ultrasonography for all lambs on farm, and with whole-body computed tomography (CT) scans for a subgroup of 18 infected lambs. Lambs achieved a high growth rate, including infected ones despite their high worm burden (confirmed at necropsy in the subgroup). As expected, lambs from the resistant (R) line were less infected than those from the susceptible (S) line. However, the clear pathogenic effects observed on muscular growth and voluntary feed intake were similar between lines. In contrast, a line difference in body fat was supported both by dorsal and volumetric CT measurements. Specifically, lower fat in the R line compared with the S line was observed equally in infected and uninfected groups, thus providing evidence for a constitutive cost of host resistance. Although this cost is not necessarily disadvantageous in nutrient-rich environments exposing animals to excess fat deposition, its consequences in nutrient-scarce environments may be important to promote sustainable breeding strategies for host resistance.

Eosinophils are bone marrow-derived granulocytes that are traditionally associated with type 2 immune responses, such as those that occur during parasite infections and allergy. Emerging evidence demonstrates the remarkable functional plasticity of this elusive cell type and its pleiotropic functions in diverse settings. Eosinophils broadly contribute to tissue homeostasis, host defence and immune regulation, predominantly at mucosal sites. The scope of their activities primarily reflects the breadth of their portfolio of secreted mediators, which range from cytotoxic cationic proteins and reactive oxygen species to multiple cytokines, chemokines and lipid mediators. Here, we comprehensively review basic eosinophil biology that is directly related to their activities in homeostasis, protective immunity, regeneration and cancer. We examine how dysregulation of these functions contributes to the physiopathology of a broad range of inflammatory diseases. Furthermore, we discuss recent findings regarding the tissue compartmentalization and adaptation of eosinophils, shedding light on the factors that likely drive their functional diversification within tissues.

Eosinophils contribute to metabolic homeostasis and airway hyperresponsiveness, but their specific role in obesity-related airway hyperresponsiveness remains unclear. To address this, we used transgenic mice that overexpress interleukin-5 (IL-5) in peripheral T cells (+IL-5T) and wild-type controls. On a normal diet, +IL-5T and wild-type mice have similar body weight, body fat, and airway nerve-mediated reflex bronchoconstriction in response to inhaled serotonin. Feeding wild-type mice a 61.6% high-fat diet resulted in significantly increased body weight, body fat, fasting glucose, fasting insulin, and reflex bronchoconstriction induced by serotonin, which was blocked by vagotomy. In contrast, +IL-5T mice on a high-fat diet gained less body weight and fat than wild-type mice on the same diet and did not exhibit potentiation in fasting glucose, fasting insulin, or reflex bronchoconstriction induced by serotonin. Compared with wild-type mice, +IL-5T mice on normal diet had significantly more adipose tissue eosinophils, and this was further increased by high-fat diet. High-fat diet did not increase adipose tissue eosinophils in wild-type mice. Our findings suggest that adipose tissue eosinophils may play a role in regulating body fat, thereby reducing insulin, which is a mediator of obesity-related airway hyperresponsiveness. Thus, our data indicate adipose tissue eosinophils may be an important avenue for research in obesity-related asthma.NEW & NOTEWORTHY This study investigates how eosinophils influence systemic metabolism and airway function in obesity. Known for their immune functions, eosinophils also mitigate obesity-related hyperinsulinemia, reducing airway hyperresponsiveness in obese mice models. The findings suggest potential therapeutic strategies targeting the intricate interplay among neurons, eosinophils, and the endocrine system to alleviate asthma in obesity. This research provides novel insights into the critical neuro-immune-endocrine interactions essential for managing obesity-related asthma.

Asthma is a chronic inflammatory lung disease with high prevalence, making it one of the most common chronic conditions worldwide. Its pathophysiology is influenced by a range of genetic and environmental factors, resulting in a complex and heterogeneous disease profile. Asthma is primarily associated with a type 2 (T2) immune response, though non-T2 endotypes also contribute to disease pathology. Generally, asthma is characterized by the infiltration and activation of various cell types, including dendritic cells, eosinophils, innate lymphoid cells, lymphocytes, mast cells, and neutrophils, which participate in T1, T2, and T17 immune responses. Despite advances in understanding, many questions remain unresolved. Therefore, emerging omic techniques, such as single-cell RNA sequencing (scRNA-seq), offer novel insights into the underlying mechanisms of asthma and the roles of these immune cells. Recent scRNA-seq studies in asthma have identified multiple novel immune cell subtypes and clusters, suggesting their potential functions in disease pathology. The rapid advancement of scRNA-seq technology now enables in-depth investigation of individual cells within tissues, allowing for precise cell-type classification and detailed molecular profiling. Nonetheless, certain limitations persist, which require further refinement in future studies.

Although obesity-related asthma is associated with worse asthma outcomes, optimal treatment approaches for this complex phenotype are still largely unavailable. This state-of-the-art review article synthesizes evidence for existing and emerging treatment approaches for obesity-related asthma and highlights pathways that offer potential targets for novel therapeutics. Existing treatments targeting insulin resistance and obesity, including metformin and GLP-1 (glucagon-like-peptide 1) receptor agonists, have been associated with improved asthma outcomes, although GLP-1R agonist data in asthma are limited to individuals with comorbid obesity. Monoclonal antibodies approved for treatment of moderate to severe asthma generally appear to be effective in individuals with obesity, although this is based on retrospective or secondary analysis of clinical trials; moreover, although most of these asthma biologics are approved for use in the pediatric population, the impact of obesity on their efficacy has not been well studied in youth. Potential therapeutic targets being investigated include IL-6, arginine metabolites, nitro-fatty acids, and mitochondrial antioxidants, with clinical trials for each currently underway. Potential therapeutic targets include adipose tissue eosinophils and the GLP-1-arginine-advanced glycation end products axis, although data in humans are still needed. Finally, transcriptomic and epigenetic studies of "obese asthma" demonstrate enrichment of IFN-related signaling pathways, Rho-GTPase pathways, and integrins, suggesting that these too could represent future treatment targets. We advocate for further study of these potential therapeutic mechanisms and continued investigation of the distinct inflammatory pathways characteristic of obesity-related asthma, to facilitate effective treatment development for this unique asthma phenotype.

Obesity has emerged as a prominent global public health concern, leading to the development of numerous metabolic disorders such as cardiovascular diseases, type-2 diabetes mellitus (T2DM), sleep apnea and several system diseases. It is widely recognized that obesity is characterized by a state of inflammation, with immune cells-particularly macrophages-playing a significant role in its pathogenesis through the production of inflammatory cytokines and activation of corresponding pathways. In addition to their immune functions, macrophages have also been implicated in lipogenesis. Additionally, the mitochondrial disorders existed in macrophages commonly, leading to decreased heat production. Meantime, adipocytes have mitochondrial dysfunction and damage which affect thermogenesis and insulin resistance. Therefore, enhancing our comprehension of the role of macrophages and mitochondrial dysfunction in both macrophages and adipose tissue will facilitate the identification of potential therapeutic targets for addressing this condition.

Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum. MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.

Introduction: Worldwide, asthma is the most common non-communicable respiratory disease and causes considerable morbidity and mortality. Most people with asthma can be treated effectively with low-dose medications if these are taken correctly and regularly. Around 10% of people with asthma have an uncontrolled form of the disease or can only achieve control with high-dose medications, incurring disproportionately high health care costs. Areas Covered: PubMed and personal archives were searched for relevant articles on the definition, management and pharmacotherapy of severe asthma. The WHO classification of severe asthma and the treatment levels encompassed in the definition are discussed. Most children and young people referred for consideration of 'beyond-guidelines therapy' can in fact be managed on standard treatment after a multi-disciplinary team assessment focusing on ensuring correct basic management, and these steps are described in detail. Options for those with true therapy-resistant asthma are described. These include monoclonal antibodies, most of which target type 2 inflammation. Expert Opinion: Getting the basics right is still the most important aspect of asthma care. For those with severe, therapy-resistant asthma, an increasing number of life-transforming monoclonals have been developed, but there is still little understanding of, and a paucity of treatment options for, non-eosinophilic asthma.

There is considerable evidence that the immune system plays a role in hypertension, however this role is not fully characterized. Our previous studies demonstrated that mesenteric perivascular adipose tissue (mPVAT) harbors a large T cell population, which is a cell type identified as contributing to hypertension. In the present study, we tested the hypothesis that soluble mediators in mPVAT influence T cell function just prior to the development of hypertension. Toward this end, we utilized a unique model of hypertension in which Dahl S rats on a high fat (HF) diet develop hypertension. We found that conditioned media (CM) from mPVAT from healthy Dahl S rats on control diet buffers T cell activation, however, mPVAT-CM from Dahl S rats on a HF diet markedly increased inflammatory cytokine induction (IFNγ, GM-CSF and IL-17a) by activated T cells. These cytokines are known to promote activation of macrophages and neutrophils, among other effects. Conversely, the anti-inflammatory cytokine, IL-10, was not different between the groups, suggesting the effect is selective for inflammatory cytokines. Furthermore, we conducted bulk RNA-seq on activated T cells cultured in mPVAT-CM from Dahl S rats on either control (CTL) or HF diet for 10 weeks. In accordance with the cytokine analysis, mPVAT-CM from HF diet-fed rats significantly upregulated many genes associated with IFNγ/IL-17 induction, whereas Th2/Treg-associated genes were downregulated. Taken together, these data strongly suggest soluble mediators from mPVAT influence T cell inflammatory status and may promote Th1/Th17 differentiation preceding the development of hypertension triggered by HF diet.

The skin serves as a complex barrier organ populated by tissue-resident macrophages (TRMs), which play critical roles in defense, homeostasis, and tissue repair. This review examines the functions of dermis resident TRMs in different inflammatory settings, their embryonic origins, and their long-term self-renewal capabilities. We highlight the M2-like phenotype of dermal TRMs and their specialized functions in perivascular and perineuronal niches. Their interactions with type 2 immune cells, autocrine cytokines such as IL-10, and their phagocytic clearance of apoptotic cells have been explored as mechanisms for M2-like dermal TRM self-maintenance and function. In conclusion, we address the need to bridge murine models with human studies, with the possibility of targeting TRMs to promote skin immunity or restrain cutaneous pathology.

Eosinophils have traditionally been viewed as pathological effector cells primarily involved in antiparasitic and allergic immune reactions; however, it is becoming increasingly apparent that eosinophils are multifaceted leukocytes that contribute to a variety of roles in both health and disease. Recent research shows that eosinophils play important immunoregulatory roles across various tissue sites including the gastrointestinal tract, adipose tissue, lung, liver, heart, muscles, thymus and bone marrow. With recent advances in our knowledge and appreciation of eosinophil immunoregulatory functions at these tissue sites, as well as emerging research demonstrating the existence of distinct subsets of eosinophils, a review of this topic is timely. Although some questions remain regarding eosinophil function and heterogeneity, this review summarizes the contemporary understanding of the immunoregulatory roles of eosinophils across various tissues and discusses the latest research on eosinophil heterogeneity and subsets.

Previously, eosinophils were primarily regarded as effector toxic cells involved in allergic diseases and parasitic infections. Nevertheless, new research has shown that eosinophils are diverse and essential for immune regulation and tissue homeostasis. Their functional plasticity has been observed in patients with inflammatory diseases, cancer, infections, and other disorders. Although eosinophils are infrequently observed within the liver during periods of homeostasis, they are recruited to the liver in various liver diseases, including liver parasitosis, acute liver injury, autoimmune liver disease, and hepatocellular carcinoma. Furthermore, eosinophils have demonstrated the capacity to promote liver regeneration. This article explores the multifaceted roles of eosinophils in liver diseases, aiming to provide insights that could lead to more effective clinical therapies for these conditions.

This review provides an overview of evidence supporting the existence of distinct homeostatic and inflammatory eosinophil subpopulations in health and disease. Particular emphasis is placed on describing the phenotypic and functional roles of these eosinophil subtypes in asthma, as well as the phenotypic changes induced by clinical therapy with the anti-IL-5 biologic agent, mepolizumab. Improved understanding of distinct eosinophil phenotypes may enable targeting of select subpopulations in the treatment of patients with type 2 inflammatory diseases such as asthma.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area.

Identifying new molecular therapies targeted at the severe hepatic fibrosis associated with the granulomatous immune response to Schistosoma mansoni infection is essential to reduce fibrosis-related morbidity/mortality in schistosomiasis. In vitro cell activation studies suggested the lipid molecule prostaglandin D2 (PGD2) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD2 and its cognate receptor DP2 in vivo, impairment of PGD2 synthesis by HQL-79 (an inhibitor of the H-PGD synthase) or DP2 receptor inhibition by CAY10471 (a selective DP2 antagonist) were used against the fibrotic response of hepatic eosinophilic granulomas of S. mansoni infection in mice. Although studies have postulated PGD2 as a fibrogenic molecule, HQL-79 and CAY10471 amplified, rather than attenuated, the fibrotic response within schistosome hepatic granulomas. Both pharmacological strategies increased hepatic deposition of collagen fibers - an unexpected outcome accompanied by further elevation of hepatic levels of the pro-fibrotic cytokines TGF-β and IL-13 in infected animals. In contrast, infection-induced enhanced LTC4 synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD2-directed maneuvers, antagonism of cysteinyl leukotriene receptors CysLT1 by MK571 also promoted enhancement of TGF-β and IL-13, indicating a key down-regulatory role for endogenous LTC4 in schistosomiasis-induced liver fibrosis. An ample body of data supports the role of S. mansoni-driven DP2-mediated activation of eosinophils as the source of LTC4 during infection, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals in parallel to a reduction in cysteinyl leukotrienes levels; (ii) peritoneal eosinophils were identified as the only cells producing LTC4 in PGD2-mediated S. mansoni-induced infection; (iii) the magnitude of hepatic granulomatous eosinophilia positively correlates with S. mansoni-elicited hepatic content of cysteinyl leukotrienes, and (iv) isolated eosinophils from S. mansoni-induced hepatic granuloma synthesize LTC4 in vitro in a PGD2/DP2 dependent manner. So, our findings uncover that granulomatous stellate cells-derived PGD2 by activating DP2 receptors on eosinophils does stimulate production of anti-fibrogenic cysLTs, which endogenously down-regulates the hepatic fibrogenic process of S. mansoni granulomatous reaction - an in vivo protective function which demands caution in the future therapeutic attempts in targeting PGD2/DP2 in schistosomiasis.

The global prevalence of type 2 diabetes mellitus (T2D) is increasing rapidly, with an anticipated 600 million cases by 2035. While infectious diseases such as helminth infections have decreased due to improved sanitation and health care, recent research suggests a link between helminth infections and T2D, with helminths such as Schistosoma, Nippostrongylus, Strongyloides, and Heligmosomoides potentially mitigating or slowing down T2D progression in human and animal models. Helminth infections enhance host immunity by promoting interactions between innate and adaptive immune systems. In T2D, type 1 immune responses are suppressed and type 2 responses are augmented, expanding regulatory T cells and innate immune cells, particularly type 2 immune cells and macrophages. This article reviews recent research shedding light on the favorable effects of helminth infections on T2D. The potential defense mechanisms identified include heightened insulin sensitivity and reduced inflammation. The synthesis of findings from studies investigating parasitic helminths and their derivatives underscores promising avenues for defense against T2D.

Eosinophils, recognized for their immune and remodeling functions and participation in allergic inflammation, have recently garnered attention due to their impact on host metabolism, especially in the regulation of adipose tissue. Eosinophils are now known for their role in adipocyte beiging, adipokine secretion, and adipose tissue inflammation. This intricate interaction involves complex immune and metabolic processes, carrying significant implications for systemic metabolic health. Importantly, the interplay between eosinophils and adipocytes is bidirectional, revealing the dynamic nature of the immune-metabolic axis in adipose tissue. While the homeostatic regulatory role of eosinophils in adipose tissue is appreciated, this relationship in the context of obesity or allergic inflammation is much less understood. Mechanistic details of eosinophil-adipose interactions, especially the direct regulation of adipocytes by eosinophils, are also lacking. Another poorly understood aspect is the metabolism of the eosinophils themselves, encompassing metabolic shifts during eosinophil subset transitions in different tissue microenvironments, along with potential effects of host metabolism on the programming of eosinophil hematopoiesis and the resulting plasticity. This review consolidates recent research in this emerging and fascinating frontier of eosinophil investigation, identifying unexplored areas and presenting innovative perspectives on eosinophil biology in the context of metabolic disorders and associated health conditions, including asthma.

Asthma affects 25 million Americans, and recent advances in treatment are effective for only a portion of severe asthma patients. TREM-1, an innate receptor that canonically amplifies inflammatory signaling in neutrophils and monocytes, plays a central role in regulating lung inflammation. It is unknown how TREM-1 contributes to allergic asthma pathology. Utilizing a murine model of asthma, flow cytometry revealed TREM-1+ eosinophils in the lung tissue and airway during allergic airway inflammation. TREM-1 expression was restricted to recruited, inflammatory eosinophils. Expression was induced on bone marrow-derived eosinophils by incubation with interleukin 33, lipopolysaccharide, or granulocyte-macrophage colony-stimulating factor. Compared to TREM-1- airway eosinophils, TREM-1+ eosinophils were enriched for proinflammatory gene sets, including migration, respiratory burst, and cytokine production. Unexpectedly, eosinophil-specific ablation of TREM-1 exacerbated airway interleukin (IL) 5 production, airway MUC5AC production, and lung tissue eosinophil accumulation. Further investigation of transcriptional data revealed apoptosis and superoxide generation-related gene sets were enriched in TREM-1+ eosinophils. Consistent with these findings, annexin V and caspase-3/7 staining demonstrated higher rates of apoptosis among TREM-1+ eosinophils compared to TREM-1- eosinophils in the inflammatory airway. In vitro, Trem1/3-/- bone marrow-derived eosinophils consumed less oxygen than wild-type in response to phorbol myristate acetate, suggesting that TREM-1 promotes superoxide generation in eosinophils. These data reveal protein-level expression of TREM-1 by eosinophils, define a population of TREM-1+ inflammatory eosinophils, and demonstrate that eosinophil TREM-1 restricts key features of type 2 lung inflammation.

Development of type 2 diabetes mellitus (T2DM) is associated with low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via the production of type 2 cytokines. Here, we demonstrate that CB2, a G-protein-coupled receptor (GPCR) and member of the endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB2 engagement on VAT ILC2s in a T2DM model. Our results show that CB2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin resistance. Our mechanistic studies reveal that the therapeutic effects of CB2 are mediated through activation of the AKT, ERK1/2, and CREB pathways on ILC2s. The results reveal that the CB2 agonist can serve as a candidate for the prevention and treatment of T2DM.

Polycystic ovary syndrome (PCOS) is associated with a low-grade inflammation, but it is unknown how hyperandrogenism, the hallmark of PCOS, affects the immune system. Using a PCOS-like mouse model, it is demonstrated that hyperandrogenism affects immune cell populations in reproductive, metabolic, and immunological tissues differently in a site-specific manner. Co-treatment with an androgen receptor antagonist prevents most of these alterations, demonstrating that these effects are mediated through androgen receptor activation. Dihydrotestosterone (DHT)-exposed mice displayed a drastically reduced eosinophil population in the uterus and visceral adipose tissue (VAT). A higher frequency of natural killer (NK) cells and elevated levels of IFN-γ and TNF-α are seen in uteri of androgen-exposed mice, while NK cells in VAT and spleen displayed a higher expression level of CD69, a marker of activation or tissue residency. Distinct alterations of macrophages in the uterus, ovaries, and VAT are also found in DHT-exposed mice and can potentially be linked to PCOS-like traits of the model. Indeed, androgen-exposed mice are insulin-resistant, albeit unaltered fat mass. Collectively, it is demonstrated that hyperandrogenism causes tissue-specific alterations of immune cells in reproductive organs and VAT, which can have considerable implications on tissue function and contribute to the reduced fertility and metabolic comorbidities associated with PCOS.

Obesity-induced chronic low-grade inflammation, also known as metaflammation, results from alterations of the immune response in metabolic organs and contributes to the development of fatty liver diseases and type 2 diabetes. The diversity of tissue-resident leukocytes involved in these metabolic dysfunctions warrants an in-depth immunophenotyping in order to elucidate disease etiology. Here, we present a 30-color, full spectrum flow cytometry panel, designed to (i) identify the major innate and adaptive immune cell subsets in murine liver and white adipose tissues and (ii) discriminate various tissue-specific myeloid subsets known to contribute to the development of metabolic dysfunctions. This panel notably allows for distinguishing embryonically-derived liver-resident Kupffer cells from newly recruited monocyte-derived macrophages and KCs. Furthermore, several adipose tissue macrophage (ATM) subsets, including perivascular macrophages, lipid-associated macrophages, and pro-inflammatory CD11c+ ATMs, can also be identified. Finally, the panel includes cell-surface markers that have been associated with metabolic activation of different macrophage and dendritic cell subsets. Altogether, our spectral flow cytometry panel allows for an extensive immunophenotyping of murine metabolic tissues, with a particular focus on metabolically-relevant myeloid cell subsets, and can easily be adjusted to include various new markers if needed.

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.

There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.