In the United States, roughly one out of every eight couples, or 7.5 million women, experience challenges related to conceiving or maintaining a pregnancy. The body's immune response is vital during pregnancy. T cells, natural killer (NK) cells, B cells, and macrophages (MQ) are immune cells in the female reproductive tract. They are in charge of maintaining tissue homeostasis and regulating the immune system's response to invasive pathogens. Failure to regulate these immune cells might result in inflammation, which reduces fertility. The immune system modulation of pregnancy loss has been studied with intralipid, intravenous immunoglobulin (IVIG), and paternal leukocyte vaccination. A concentrated antibody called intravenous immunoglobulin (IVIG) is utilized as a biological agent to treat autoimmune, viral, and inflammatory diseases and some immunodeficiencies. The main objective of this treatment is to restore a damaged immune system. IgGs, through binding to specific antigens, promote the innate immunity's cellular and humoral immune response by activating complements and binding to Fc receptors of several immune cells. Contrariwise, IVIG regulates pathogenic autoimmunity in animal models, including skin-blister diseases, nephrotoxic nephritis, and K/BxN arthritis. IVIG has, therefore, been of great interest as an immune modulator in several immune disorders. This review aims to investigate the immunological reasons of reproductive failure, focusing on the immunomodulatory effects of IVIG in its treatment.

Diabetic cardiomyopathy is a notable microvascular complication of diabetes, characterized primarily by myocardial fibrosis and functional abnormalities. Long-term hyperglycemia induces excessive activation and recruitment of immune cells and triggers the cascade of inflammatory responses, resulting in systemic and local cardiac inflammation. Emerging evidence highlights the significant roles of immunology in modulating the pathology of diabetic cardiomyopathy. As the primary effectors of inflammatory reactions, immune cells are consistently present in cardiac tissue and can be recruited under pathological hyperglycemia circumstances. A disproportionate favor to proinflammatory types of immune cells and the increased proinflammatory cytokine levels mediate fibroblast proliferation, phenotypic transformation, and collagen synthesis and ultimately rise to cardiac fibrosis and hypertrophy. Meanwhile, the severity of cardiac fibrosis is also strongly associated with the diverse phenotypes and phenotypic alterations of the immune cells, including macrophages, dendritic cells, mast cells, neutrophils, and natural killer cells in innate immunity and CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes in adaptive immunity. In this review, we synthesized the current analysis of the critical role played by the immune system and its components in the progression of diabetic cardiomyopathy. Finally, we highlight preclinical and clinical immune targeting strategies and translational implications.

Type 2 Diabetes Mellitus (T2DM) is a rapidly growing global health issue characterized by insulin resistance and chronic inflammation. Beyond regulating glucose homeostasis, insulin plays a pivotal role in modulating immune cell function, linking metabolic dysregulation with immune responses. This review examines the intricate relationship between insulin resistance and immune dysfunction in T2DM, focusing on how impaired insulin signaling pathways, particularly PI3K/Akt and MAPK, contribute to immune cell activation, proliferation, and chronic inflammation. Insulin resistance impacts immune cells such as T cells, B cells, macrophages, and neutrophils, leading to an imbalance between pro-inflammatory and anti-inflammatory responses. Elevated pro-inflammatory cytokines (eg, TNF-α, IL-6) and adipokines (eg, leptin, resistin) exacerbate insulin resistance, promoting a vicious cycle of metabolic and immune dysregulation. This interplay contributes to the chronic low-grade inflammation that underlies T2DM pathogenesis, further impairing insulin signaling and glucose metabolism. Restoration of insulin sensitivity is, therefore, a critical step toward correcting immune imbalance in insulin-resistant states like T2DM. Therapeutic approaches that reduce inflammation could also support improvements in insulin sensitivity, addressing both metabolic and immune disturbances simultaneously. The review also explores therapeutic strategies, including insulin therapy, targeting insulin signaling pathways, and lifestyle interventions. Insulin therapy can reduce pro-inflammatory cytokine production and enhance anti-inflammatory responses, although challenges such as potential immune suppression and hyperinsulinemia remain. Targeting key signaling pathways and transcription factors offers promising avenues for modulating immune responses, while lifestyle interventions, such as dietary modifications, physical activity, and weight management, can improve insulin sensitivity and reduce inflammation. By understanding the dual role of insulin in regulating both metabolic and immune functions, this review underscores the importance of addressing immune dysfunction as part of comprehensive T2DM management. Targeting the interconnected pathways of insulin signaling and immune regulation could lead to more effective therapeutic approaches, ultimately improving patient outcomes and reducing disease complications.

Diabetic kidney disease (DKD) is the most common cause of kidney failure, characterized by chronic inflammation and fibrosis. The complement system is increasingly implicated in the development and progression of diabetic nephropathy. The important complement anaphylatoxins C3a and C5a are key mediators of the innate immune system, which regulates cellular inflammation, oxidative stress, mitochondrial homeostasis and tissue fibrosis. This review summarizes the involvement of anaphylatoxins in the pathogenesis of diabetic kidney disease, highlights their important roles in the pathophysiologic changes of glomerulopathy, tubulointerstitial damage and immune cell infiltration, and discusses the modulatory effects of new anti-diabetic drugs acting on the complement system. Based on available clinical data and findings from the preclinical studies of complement blockade, anaphylatoxin-targeted therapeutics may become a promising approach for patients with DKD in the future.

Adropin is a secreted peptide encoded by the energy homeostasis-associated gene (ENHO), located chromosome 9p13.3, with a conserved amino acid sequence across humans and mice. Its expression is regulated by various factors, including fat, LXRα, ERα, ROR, and STAT3. Adropin plays a critical role in glucose and lipid metabolism, as well as insulin resistance, by modulating multiple signaling pathways that contribute to the reduction of obesity and the improvement of blood lipid and glucose homeostasis. Additionally, it influences immune cells and inflammation, exerting anti-inflammatory effects across various diseases. While extensive research has summarized the regulation of cellular energy metabolism by adropin, limited studies have explored its role in immune regulation and inflammation. To enhance the understanding of adropin's immune-modulating and anti-inflammatory mechanisms, this review synthesizes recent findings on its effects in conditions such as atherosclerosis, diabetes, fatty liver, non-alcoholic hepatitis, and inflammation. Furthermore, the review discusses the current research limitations and outlines potential future directions for adropin-related investigations. It is hoped that ongoing research into adropin will contribute significantly to the advancement of medical treatments for various diseases.

Hepatic immune imbalance is crucial for driving metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the role of hepatic regulatory T cells (Tregs) in MASLD initiation and the mechanisms responsible for their change are not completely understood.

A mouse model subjected to a short-term high-fat diet (HFD) to mimic early steatosis, along with liver biopsy samples from patients with simple steatosis, and macrophage-specific Notch1-knockout mice (Notch1M-KO), were used to investigate the role of Tregs in early MASLD and the effect of hepatic macrophage Notch1 signaling on Treg frequency. The miRNAs correlated with Treg differentiation were analyzed using exosomal miRNA sequencing.

A decrease in Tregs contributed to HFD-induced hepatic steatosis and insulin resistance (five/group/time point, p <0.001). Remarkably, the frequency of Tregs was negatively correlated with Notch1 activation in hepatic macrophages during hepatic steatosis (38/group, r = -0.735, p <0.001). Furthermore, Notch1 deficiency attenuated hepatic lipid deposition and reversed Treg levels (five/group, p <0.01 and <0.05, respectively). Moreover, Treg depletion in Notch1M-KO mice greatly diminished the ameliorative effect of macrophagic Notch1 deletion on hepatic steatosis. Mechanistically, macrophage Notch1 activation increased the level of exosomal miR-142a-3p (by one- to two- fold), impairing Treg differentiation by targeting transforming growth factor beta receptor 1 (TGFBR1) on T cells. Consistently, HFD-fed Notch1M-KO mice exhibited reduced miR-142a-3p levels, elevated TGFBR1 expression on T cells, and increased Treg frequency in the liver.

These findings highlight the crucial role of hepatic Tregs during the early stage of MASLD and add a novel, non-negligible pathway for macrophage involvement in hepatic steatosis. We identify a previously unrecognized molecular mechanism involving the macrophage Notch1/exosomal miR-142a-3p/TGFBR1 pathway in regulating Treg differentiation, providing a rationale for refined therapeutic strategies for MASLD.

The immune mechanisms driving MASLD progression, particularly during the early stages of disease, are not fully understood, which limits the development of effective interventions. This study elucidated a novel mechanism by which hepatic macrophage Notch1 signaling modulated Tregs through the exosomal miR-142a-3p/TGFBR1 axis, contributing to the progression of MASLD. These findings provide a rationale for a potential immunological approach to treat MASLD in the future.

To investigate immunometabolic associations of CD4+ T cell phenotypes with gestational diabetes mellitus (GDM).

A nested case-control study was conducted comprising 53 pairs of GDM patients and matched controls within a prospective cohort. Metabolomic signatures related to both CD4+ T cell phenotypes and glycemic traits among pregnant women were investigated by weighted gene co-expression network analysis (WGCNA). Multivariable-adjusted generalized linear models were used to explore the associations of CD4+ T cell phenotypes and selected metabolites with GDM. Mediation analysis was conducted to evaluate the mediating effect of selected metabolites on the relationship between CD4+ T cell phenotypes and glycemic traits.

Higher levels of Treg cells (OR per SD increment (95%CI): 0.57 (0.34, 0.95), p = 0.031) and increased expression of Foxp3 (OR per SD increment (95%CI): 0.59 (0.35, 0.97), p = 0.039) and GATA3 (OR per SD increment (95%CI): 0.42 (0.25, 0.72), p = 0.002) were correlated with a decreased risk of GDM. Plasma pyruvaldehyde, S-adenosylhomocysteine (SAH), bergapten, and 9-fluorenone mediated the association between Tregs and fasting plasma glucose (FPG), with mediation proportions of 46.9%, 39.6%, 52.4%, and 56.9%, respectively.

Treg cells and Foxp3 expressions were inversely associated with GDM risk, with potential metabolic mechanisms involving metabolites such as pyruvaldehyde and SAH.

Patients with coronary artery disease (CAD) combined with type 2 diabetes mellitus (T2DM) develop serious atherosclerotic and diffuse lesions. Inadequate numbers and the dysfunction of CD4+CD25+Foxp3+regulatory T lymphocytes (Treg cells) are common mechanisms underlying the immunopathological damage in CAD and T2DM.

We aimed to explore Treg cell changes in patients with CAD complicated with T2DM and to investigate the association between Treg cells and the severity of CAD.

A total of 257 participants were included in the study, divided into a healthy control group (HC, n = 63), CAD group (n = 106), and CAD complicated with T2DM group (CAD+T2DM, n = 88). Flow cytometry detected Treg cell levels, and serum IL-10, IL-6, and ELISA detected TGF-β.

The sample for this study consisted of 170 males and 87 females, with 88 (34.24 %) participants having diabetes and 169 (65.76 %) without diabetes. The proportion of circulating Treg cells was lower in the CAD and CAD+T2DM groups than in the HC group, and it was lower in the CAD+T2DM group than in the CAD group. The plasma levels of IL-10 and TGF-β were lower in the CAD than in the HC group, and the levels in the CAD+T2DM group were significantly lower than those in the CAD group. However, the plasma IL-6 level changed in the opposite direction. Gensini's score was negatively correlated with Treg cells (R = - 0.57, P < .05). Subgroup analyses and interaction analyses showed that the association of Treg with the Gensini score was robust.

The level of Treg cells was an independent protective factor for patients with CAD and T2DM and was negatively correlated with the Gensini score. Therefore, Treg cells may be used as therapeutic targets for CAD with T2DM patients.

The global incidence of type 2 diabetes (T2D) is rapidly increasing, with retinopathy being its most common complication and a leading cause of preventable blindness. Although the precise mechanisms involved in the development of diabetic retinopathy (DR) are not fully understood, defective immunomodulation is a recognized key factor in its pathophysiology. Regulatory T cells (Treg) regulate inflammation and promote regeneration, and while they are known to have important anti-inflammatory and neuroprotective roles in other tissues, including central nervous system, their role in the diabetic retina remains largely unknown. The aim of the present study is to examine the effect of Treg expansion of retinal neurodegeneration, an early event in the pathogenesis of DR.

Treg expansion was achieved by co-injecting recombinant mouse IL-2 with anti-IL-2 monoclonal antibody or its isotype in db/db mice as an established model of T2D. Treg expansion was confirmed via flow cytometry in blood, spleen, and retina. Fundus angiography was performed in the days prior to animal sacrifice at 18 weeks. To study the effect of Tregs on retinal neurons, glia and vascular permeability, immunohistochemistry against Cone-Arrestin, PKCα, synaptophysin, ChAT, TH, GFAP, Iba-1, calbindin, Brn3a, RBPMS, isolectin B4, and albumin was used. Retinal VEGF levels were measured with a magnetic bead-based immunoassay, and NLRP3, Casp1, p20 and IL-18 were analyzed by Western Blot in retinal homogenates.

There was a significant decrease in Treg in db/db mice blood. When this deficiency was corrected in db/db mice by systemic Treg expansion, there was an effective protection against retinal neurodegenerative, gliotic, inflammatory changes and vascular leakage associated with T2D. Importantly, Treg expansion did not impact the T2D phenotype in db/db mice as evaluated by blood glucose, HbA1c and circulating insulin.

Treg modulation in T2D offers a promising therapeutic approach to prevent early stages of DR. This strategy focuses on reducing neuroinflammation and mitigating the associated neuronal, glial, and vascular degenerative changes characteristic of DR.

Diabetic retinopathy (DR) continues to be the leading cause of preventable vision loss among working-aged adults, marked by immune dysregulation within the retinal microenvironment. Typically, the retina is considered as an immune-privileged organ, where circulating immune cells are restricted from entry under normal conditions. However, during the progression of DR, this immune privilege is compromised as circulating immune cells breach the barrier and infiltrate the retina. Increasing evidence suggests that vascular and neuronal degeneration in DR is largely driven by the infiltration of immune cells, particularly neutrophils, monocyte-derived macrophages, and lymphocytes. This review delves into the mechanisms and therapeutic targets associated with these immune cell populations in DR, offering a promising and innovative approach to managing the disease.

Systemic immune-inflammation index (SII) was an indicator which could reflect immune response and systemic inflammation. We aim to explore the relationship between SII and diabetic nephropathy (DN).

SII was calculated as neutrophil count × platelet count/lymphocyte count. The receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnosis power of SII. Univariate and multivariate logistic analysis were conducted to assess SII as the risk factor for DN. A restricted cubic spline model was carried out to show the nonlinear association between SII and DN.

Two hundred participants were enrolled, with an average age of 56.6 ± 13.4 years; 54% participants were categorized as DN. Spearman association analysis showed SII was positive associated with increased urinary albumin to creatinine ratio and serum creatinine, while negative associated with eGFR and serum albumin. The ROC curve revealed that the maximum area under the curve (AUC) was 0.761 (95% CI, 0.694-0.828, P < 0.001). After univariate and multivariate logistic analysis, SII (OR=1.004, P = 0.002) and serum creatinine (OR=1.146, P < 0.001) were risk factors for the occurrence of DN, while age (OR=0.920, P = 0.011) and serum albumin (OR=0.708, P < 0.001) were protective factors for the occurrence of DN. The restricted cubic spline model showed that there was a significant nonlinear association between DN incidence and continuous SII value when it exceeded 624*10ˆ 9/L.

SII is a novel diagnostic biomarker which is independently associated with DN. Further large-scale prospective studies are needed to validate our findings before SII can be considered a reliable diagnostic or prognostic tool for DN.

The prevalence of obesity and its associated metabolic disorders has emerged as one of the most significant health threats worldwide. The visceral adipose tissue regulatory T cells (VAT Treg) play an essential role in maintaining homeostasis and preventing obesity mainly by secreting Interleikin-10 (IL-10) and Transforming Growth Factor β (TGF-β). However, the mechanism that regulates VAT Treg quantity and function remains unclear. Here we elucidate the pivotal role of IL-27 signaling in sustaining the accumulation of VAT Treg cells, thereby conferring protection against obesity. We found that mice with the deficiency of IL-27 receptor Wsx1 gained more body weight and VAT weight than their wild-type littermates when fed both a normal-fat diet (NFD) and a high-fat diet (HFD). Notably, the population of VAT Treg cells was reduced in Wsx1 knockout (KO) mice, regardless of whether they were fed a normal-fat diet (NFD) or a high-fat diet (HFD). Correspondingly, the expression levels of the transcription factors FOXP3 and PPAR-γ, essential for VAT Treg function, were also diminished in Wsx1 KO mice. Taken together, our findings indicate that IL-27 signaling plays a protective role in obesity by supporting the maintenance and accumulation of VAT Treg cells.

Type 2 diabetes mellitus is a complex metabolic disorder characterized by insulin resistance and, subsequently, decreased insulin secretion. This condition is closely linked to obesity, a major risk factor that boosts the development of chronic systemic inflammation, which, in turn, is recognized for its crucial role in the onset of insulin resistance. Under conditions of obesity, adipose tissue, particularly visceral fat, becomes an active endocrine organ that releases a wide range of pro-inflammatory mediators, including cytokines, chemokines, and adipokines. These mediators, along with cluster of differentiation (CD) markers, contribute to the maintenance of systemic low-grade inflammation, promote cellular signaling and facilitate the infiltration of inflammatory cells into tissues. Emerging studies have indicated the accumulation of a new cell population in the adipose tissue in these conditions, known as myeloid-derived suppressor cells (MDSCs). These cells possess the ability to suppress the immune system, impacting obesity-related chronic inflammation. Given the limited literature addressing the role of MDSCs in the context of type 2 diabetes, this article aims to explore the complex interaction between inflammation, obesity, and MDSC activity. Identifying and understanding the role of these immature cells is essential not only for improving the management of type 2 diabetes but also for the potential development of targeted therapeutic strategies aimed at both glycemic control and the reduction in associated inflammation.

Regulatory T cells (Tregs) have protected against many cardiovascular diseases. This study was intended to explore the effect of Tregs on diabetic cardiomyopathy (DCM) using a db/db mouse model.

Eight-week-old male db/db mice were randomly divided into four groups: the control group, administered 200 μL phosphate-buffered saline; the small-dose Treg group, administered 105 Tregs; the large-dose Treg group, administered 106 Tregs; and the PC group, administered 100 μg anti-CD25 specific antibody (PC61) and 106 Tregs. After 12 weeks, mice were euthanized. Transthoracic echocardiography was carried out at the beginning and end of the experiment. Relevant basic experiments to evaluate the effects of Tregs on DCM were carried out.

Echocardiography showed that the impaired diastolic and systolic functions were significantly improved in mice administered large-dose Tregs. Large-dose Tregs significantly ameliorated myocardial hypertrophy and fibrosis, and decreased hypertrophic gene expression and collagen deposition. The protective effects of Tregs on diabetic hearts were associated with decreased oxidative stress, inflammatory response and apoptosis. In addition, Tregs promoted the activation of the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, whereas they inhibited extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase phosphorylation, which might be responsible for the cardioprotective role of Tregs against DCM.

Tregs ameliorated myocardial hypertrophy and fibrosis, improved cardiac dysfunction, and protected against DCM progression in db/db mice. The mechanisms involved a decrease of inflammatory response, oxidative stress and apoptosis, which might be mediated by phosphatidylinositol 3-kinase-protein kinase B and mitogen-activated protein kinase pathways. Hence, Tregs might serve as a promising therapeutic approach for DCM treatment.

Diabetic nephropathy (DN) presents a significant therapeutic challenge, compounded by complex pathophysiological mechanisms. Recent studies suggest Exendin-4 (Ex-4) as a potential ameliorative agent for DN, albeit with unclear mechanisms. This research investigates the effects and underlying mechanisms of Ex-4-enriched exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) on DN, focusing on their renoprotective properties and interactions with gut microbiota.

Exosomes from hUCMSCs (hUCMSCs-Exo) were loaded with Ex-4 via electroporation. A streptozotocin (STZ) -induced DN mouse model was employed to assess the therapeutic impact of these engineered exosomes. The study further explored immune cell dynamics, mainly CD4+ regulatory T (Treg) cells, using bioinformatics, flow cytometry, and the influence of gut microbiota through antibiotic treatment and specific bacterial reintroduction.

Treatment with hUCMSCs-Exo@Ex-4 significantly improved key DN markers, including blood glucose and proteinuria, alleviating kidney damage. A notable decrease in natural Treg cell infiltration in DN was observed, while Ex-4-loaded exosomes promoted CD4+ Treg cell induction. The therapeutic benefits of hUCMSCs-Exo@Ex-4 were diminished upon CD4+ Treg cell depletion, underscoring their role in this context. Notably, CD4+ Treg cell induction correlated with the presence of Prevotella species, and disruption of gut microbiota adversely affected these cells and the therapeutic efficacy of the treatment. However, the reintroduction of Prevotella strains counteracted these adverse effects.

This study elucidates a novel therapeutic mechanism of Ex-4-loaded hUCMSCs exosomes in DN, highlighting the induction of CD4+ Treg cells mediated by specific gut microbiota components. These findings underscore the potential of leveraging gut microbiota and immune cell interplay in developing effective DN treatments.

Diabetic kidney disease (DKD) is the primary contributor to renal failure and poses a severe threat to human health. Accumulating studies demonstrated that competing endogenous RNA (ceRNA) network is involved in cuproptosis and DKD progression. However, the role of cuproptosis-associated ceRNA network and immune infiltration in DKD remains largely unclear. This study aimed to investigate the cuproptosis-related ceRNA regulation network and immune infiltration in DKD.

The rat model of DKD was induced by combining the nephrectomy of the left kidney, high-fat diet, and streptozotocin. Differentially expressed genes (DEGs), miRNAs (DEMs), and lncRNAs (DELs) between normal and DKD rats were obtained. DEGs were intersected with cuproptosis-related genes (CRGs) to obtain DE-CRGs. LncRNAs and miRNAs were predicted based on the DE-CRGs, and they were intersected with DEMs and DELs, respectively. Subsequently, a cuproptosis-associated lncRNA-miRNA-mRNA network was established in DKD. In addition, the relative proportion of 22 infiltrating immune cell types in each sample was calculated, and the relationship between hub DE-CRGs and immune cells was explored.

In total, there were 429 DEGs, 22 DEMs, and 48 DELs between CON and MOD groups. Then, 73 DE-CRGs were obtained, which were significantly enriched in 22 pathways, such as MAPK signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. In addition, a core cuproptosis-related ceRNA network that included one lncRNA (USR0000B2476D), one miRNA (miR-34a-3p), and eight mRNAs (Mmp9, Pik3c3, Prom1, Snta1, Slc51b, Ntrk3, Snca, Egf) was established. In addition, 18 hub DE-CRGs were obtained. CIBERSORT algorithms showed that resting dendritic cells and resting NK cells were more infiltrated whereas regulatory T cells were less infiltrated in DKD rats than in normal rats. Spearman's correlation analysis revealed that hub DE-CRGs showed significant positive or negative correlations with naive B cells, regulatory T cells, resting NK cells, M0 macrophages, resting dendritic cells, and resting mast cells.

A ceRNA network was comprehensively constructed, and 18 hub DE-CRGs were obtained, which will provide novel insights into the pathologic mechanism elucidation and targeted therapy development of DKD.

While circulating metabolites and immune system have been increasingly linked to hypothyroidism risk, the causality underlying these associations remains largely uninterrogated. We used Mendelian randomization to identified putative causal traits for hypothyroidism via integrating omics data. Briefly, we utilized 1180 plasma metabolites and 731 immune cells traits as exposures to identify putatively causal traits for hypothyroidism in the discovery (40,926 cases) and replication cohorts (14,871 cases). By combining MR results from two large-scale cohorts, we ultimately identified 21 putatively causal traits, including five plasma metabolites and 16 immune cell traits. CD3 on CD28+ CD4+ T cell and 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (p-16:0/18:1) demonstrated the most pronounced positive and negative associations with hypothyroidism risk, respectively. The odds ratio and 95% confidence interval were 1.09 (1.07, 1.12) and 0.81 (0.75, 0.87), respectively. No evidence of horizontal pleiotropy, heterogeneity among instrumental variables or reverse causation were found for these 21 significant associations. Our study elucidates key metabolites and immune cell traits associated with hypothyroidism. These findings provide new insights into the etiology and potential therapeutic targets for hypothyroidism.

AGEs, their receptor (RAGE), and the extracellular newly identified receptor for AGEs product-binding protein (EN-RAGE) are implicated in the pathogenesis of inflammation.

We analyzed serum EN-RAGE, soluble RAGE (sRAGE), and their isoforms: endogenous secretory - esRAGE and cleaved - cRAGE concentrations in lean controls (n = 74) and in patients with obesity (n = 71) treated for three weeks with moderate calorie restriction (CR) combined with physical activity in a hospital condition.

Using the ELISA method, serum sRAGE, esRAGE, and EN-RAGE were measured before and after CR.

The serum level of sRAGE and esRAGE in patients with obesity was lower than that in non-obese individuals, contrary to cRAGE. EN-RAGE concentration was about three times higher in obese patients. Gradually, a rise in BMI resulted in sRAGE, esRAGE reduction, and EN-RAGE increase. The sRAGE concentration was sex-dependent, indicating a higher value in lean men. A moderate negative correlation was observed between BMI and all RAGE isoforms, whereas EN-RAGE displays a positive correlation. CR resulted in an expected decrease in anthropometric, metabolic, and proinflammatory parameters and EN-RAGE, but no RAGE isoforms. The ratio EN-RAGE/sRAGE was higher in obese humans than in control and was not modified by CR.

Obesity decreases sRAGE and esRAGE and increases EN-RAGE concentration. Moderate CR and physical activity by decreasing inflammation reduces EN-RAGE but is insufficient to increase sRAGE and esRAGE to the extent observed in lean patients. EN-RAGE instead of sRAGE could be helpful to indicate a better outcome of moderate dietary intervention in obese subjects.

Diabetes ranks among the most widespread diseases globally, with the kidneys being particularly susceptible to its vascular complications. The identification of proteins for pathogenesis and novel drug targets remains imperative. This study aims to investigate roles of circulating inflammatory proteins in diabetic renal complications.

Data on the proteins were derived from a genome-wide protein quantitative trait locus (pQTL) study, while data on diabetic renal complications came from the FinnGen study. In this study, proteome-wide Mendelian randomization (MR) and colocalization analyses were used to assess the relationship between circulating inflammatory proteins and diabetic renal complications.

MR approach indicated that elevated levels of interleukin 12B (IL-12B) (OR 1.691, 95%CI 1.179-2.427, P=4.34×10-3) and LIF interleukin 6 family cytokine (LIF) (OR 1.349, 95%CI 1.010-1.801, P=4.23×10-2) increased the risk of type 1 diabetes (T1D) with renal complications, while higher levels of fibroblast growth factor 19 (FGF19) (OR 1.202, 95%CI 1.009-1.432, P=3.93×10-2), fibroblast growth factor 23 (FGF23) (OR 1.379, 95%CI 1.035-1.837, P=2.82×10-2), C-C motif chemokine ligand 7 (CCL7) (OR 1.385, 95%CI 1.111-1.725, P=3.76×10-3), and TNF superfamily member 14 (TNFSF14) (OR 1.244, 95%CI 1.066-1.451, P=5.63×10-3) indicated potential risk factors for type 2 diabetes (T2D) with renal complications. Colocalization analysis supported these findings, revealing that most identified proteins, except for DNER, likely share causal variants with diabetic renal complications.

Our study established associations between specific circulating inflammatory proteins and the risk of diabetic renal complications, suggesting these proteins as targets for further investigation into the pathogenesis and potential therapeutic interventions for T1D and T2D with renal complications.

Regulatory T cells (Tregs) within the visceral adipose tissue (VAT) play a crucial role in controlling tissue inflammation and maintaining metabolic health. VAT Tregs display a unique transcriptional profile and T cell receptor (TCR) repertoire, and closely interact with adipocytes, stromal cells, and other immune components within the local VAT microenvironment. However, in the context of obesity, there is a notable decline in VAT Tregs, resulting in heightened VAT inflammation and insulin resistance. A comprehensive understanding of the biology of VAT Tregs is essential for the development of Treg-based therapies for mitigating obesity-associated metabolic diseases. Recent advancements in lineage tracing tools, genetic mouse models, and various single cell "omics" techniques have significantly progressed our understandings of the origin, differentiation, and regulation of this unique VAT Treg population at steady state and during obesity. The identification of VAT-Treg precursor cells in the secondary lymphoid organs has also provided important insights into the timing, location, and mechanisms through which VAT Tregs acquire their distinctive phenotype that enables them to function within a lipid-rich microenvironment. In this review, we highlight key recent breakthroughs in the VAT-Treg field while discussing pivotal questions that remain unanswered.

Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.

Diabetic kidney disease is one of the most severe chronic microvascular complications of diabetes and a primary cause of end-stage renal disease. Clinical studies have shown that renal inflammation is a key factor determining kidney damage during diabetes. With the development of immunological technology, many studies have shown that diabetic nephropathy is an immune complex disease, and that most patients have immune dysfunction. However, the immune response associated with diabetic nephropathy and autoimmune kidney disease, or caused by ischemia or infection with acute renal injury, is different, and has a com-plicated pathological mechanism. In this review, we discuss the pathogenesis of diabetic nephropathy in immune disorders and the intervention mechanism, to provide guidance and advice for early intervention and treatment of diabetic nephropathy.

White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.

The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. Our study is premised on the hypothesis that the dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression.

A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed.

Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM-3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed with minimal change disease (p=0.03, 0.02 and 0.002, respectively). ScRNA-seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And one of TIM-3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened.

Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression.

The interaction of dysbiosis of gut microbiota (GM) with diabetic nephropathy (DN) drew our attention and a better understanding of GM on DN might provide potential therapeutic approaches. However, the exact causal effect of GM on DN remains unknown.

We applied two-sample Mendelian Randomization (MR) analysis, including inverse variance weighted (IVW), MR-Egger methods, etc., to screen the significant bacterial taxa based on the GWAS data. Sensitivity analysis was conducted to assess the robustness of MR results. To identify the most critical factor on DN, Mendelian randomization-Bayesian model averaging (MR-BMA) method was utilized. Then, whether the reverse causality existed was verified by reverse MR analysis. Finally, transcriptome MR analysis was performed to investigate the possible mechanism of GM on DN.

At locus-wide significance levels, the results of IVW suggested that order Bacteroidales (odds ratio (OR) = 1.412, 95% confidence interval (CI): 1.025-1.945, P = 0.035), genus Akkermansia (OR = 1.449, 95% CI: 1.120-1.875, P = 0.005), genus Coprococcus 1 (OR = 1.328, 95% CI: 1.066-1.793, P = 0.015), genus Marvinbryantia (OR = 1.353, 95% CI: 1.037-1.777, P = 0.030) and genus Parasutterella (OR = 1.276, 95% CI: 1.022-1.593, P = 0.032) were risk factors for DN. Reversely, genus Eubacterium ventriosum (OR = 0.756, 95% CI: 0.594-0.963, P = 0.023), genus Ruminococcus gauvreauii (OR = 0.663, 95% CI: 0.506-0.870, P = 0.003) and genus Erysipelotrichaceae (UCG003) (OR = 0.801, 95% CI: 0.644-0.997, P = 0.047) were negatively associated with the risk of DN. Among these taxa, genus Ruminococcus gauvreauii played a crucial role in DN. No significant heterogeneity or pleiotropy in the MR result was found. Mapped genes (FDR < 0.05) related to GM had causal effects on DN, while FCGR2B and VNN2 might be potential therapeutic targets.

This work provided new evidence for the causal effect of GM on DN occurrence and potential biomarkers for DN. The significant bacterial taxa in our study provided new insights for the 'gut-kidney' axis, as well as unconventional prevention and treatment strategies for DN.

Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by changes in kidney structure and function. The natural product rosmarinic acid (RA) has demonstrated therapeutic effects, including anti-inflammation and anti-oxidative-stress, in renal damage or dysfunction. In this study, we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels. Our results demonstrated that RA significantly alleviated renal tubular epithelial injury, particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes, while attenuating the inflammatory response of macrophages, oxidative stress, and cytotoxicity of natural killer cells. These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage, oxidative stress, and inflammation, offering valuable guidance for the clinical application of RA in the treatment of DN.

Regulatory T cells (Tregs) expressing the transcription factor FoxP3 are essential for maintaining immunological balance and are a significant component of the immunosuppressive tumor microenvironment (TME). Single-cell RNA sequencing (ScRNA-seq) technology has shown that Tregs exhibit significant plasticity and functional diversity in various tumors within the TME. This results in Tregs playing a dual role in the TME, which is not always centered around supporting tumor progression as typically believed. Abundant data confirms the anti-tumor activities of Tregs and their correlation with enhanced patient prognosis in specific types of malignancies. In this review, we summarize the potential anti-tumor actions of Tregs, including suppressing tumor-promoting inflammatory responses and boosting anti-tumor immunity. In addition, this study outlines the spatial and temporal variations in Tregs function to emphasize that their predictive significance in malignancies may change. It is essential to comprehend the functional diversity and potential anti-tumor effects of Tregs to improve tumor therapy strategies.

Regulatory T cells (Tregs) residing in visceral adipose tissue (VAT) play a pivotal role in regulating tissue inflammation and metabolic dysfunction associated with obesity. However, the specific phenotypic and functional characteristics of Tregs in obese VAT, as well as the regulatory mechanisms shaping them, remain elusive. This study demonstrates that obesity selectively reduces Tregs in VAT, characterized by restrained proliferation, heightened PD-1 expression, and diminished ST2 expression. Additionally, obese VAT displays distinctive maturation of dendritic cells (DCs), marked by elevated expressions of MHC-II, CD86, and PD-L1, which are inversely correlated with VAT Tregs. In an in vitro co-culture experiment, only obese VAT DCs, not macrophages or DCs from subcutaneous adipose tissue (SAT) and spleen, result in decreased Treg differentiation and proliferation. Furthermore, Tregs differentiated by obese VAT DCs exhibit distinct characteristics resembling those of Tregs in obese VAT, such as reduced ST2 and IL-10 expression. Mechanistically, obesity lowers IL-33 production in VAT DCs, contributing to the diminished Treg differentiation. These findings collectively underscore the critical role of VAT DCs in modulating Treg generation and shaping Treg phenotype and function during obesity, potentially contributing to the regulation of VAT Treg populations.

Diabetic kidney disease (DKD) is one of the prominent microvascular complications of diabetes and the leading cause of end-stage renal disease. Inflammation plays a crucial role in the development and progression of DKD. Currently, only a few studies depict the landscape of infiltrating immune cells and their potential regulatory network in DKD. To gain a better understanding of the role of immune cells in the renal microenvironment, we sought to reveal the profile of infiltrating immune cells and their potential regulatory network in DKD.

We obtained the transcriptomes and the corresponding clinical data of 19 DKD and 25 control samples from the Gene Expression Omnibus and Nephroseq databases, respectively. Thereafter, we conducted an analysis on the infiltrating immune cells and identified immune-related differentially expressed genes through bioinformatics. Finally, correlation analyses among immune cells, immune genes, and clinical manifestations were performed, and differentially infiltrating immune cell subsets were verified through multiplex immunofluorescence staining.

We demonstrated the landscape of infiltrating immune cells in patients with DKD and identified the top five hub immune regulatory genes (C3, IL7R, TYROBP, BMP2, and CXCL6). Three of the core genes (C3, BMP2, and CXCL6) were significantly correlated with the estimated glomerular filtration rate. Through multiplex immunofluorescence staining, we verified that macrophage numbers were remarkably elevated, whereas Treg cells were remarkably reduced in diabetic kidney tissues. Th2 cells were scarce in the kidney tissue.

Collectively, our findings shed light on new, possible therapeutic strategies for DKD, from an immune microenvironment perspective.

The impact of inflammatory factors on the risk of diabetic nephropathy (DN) is inconsistent. Two-sample Mendelian randomization (MR) analyses were used to detect the causal role of inflammatory factors in DN risk.

Inflammatory factor GWAS summary data were collected from a meta-analysis including 8,293 Finnish participants, and DN information was extracted from a GWAS of 213,746 individuals from FinnGen. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) outlier test was used for the removal of horizontal pleiotropic outliers. Multivariable MR analysis was also used to adjust for pleiotropy.

IFN-γ [ORIVW: 1.33; 95% CI: 1.09-1.63; p=0.005] and SCF [ORIVW: 1.25, 1.02-1.52; p = 0.027] were associated with an increased risk of DN. MIP1b [ORIVW: 0.92; 95% CI: 0.85-0.98; p = 0.022] and IL-16 [ORIVW: 0.89, 0.81-0.99; p = 0.043] showed negative associations with the risk of DN. We validated our MR results with MR-PRESSO analyses. Significant horizontal pleiotropy was not found. Moreover, in the multivariable MR analysis, the associations between cytokines and DN risk remained.

Our MR results based on genetic data contribute to a better understanding of the pathogenesis of DN and provide evidence for a causal effect of inflammatory factors on DN. These findings support targeting specific inflammatory factors to alleviate DN risk.

Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.

Tissue regulatory T cells (Tregs) exert pivotal functions in both immune and metabolic regulation, maintaining local tissue homeostasis, integrity, and function. Accordingly, Tregs play a crucial role in controlling obesity-induced inflammation and supporting efficient muscle function and repair. Depending on the tissue context, Tregs are characterized by unique transcriptomes, growth, and survival factors and T cell receptor (TCR) repertoires. This functional specialization offers the potential to selectively target context-specific Treg populations, tailoring therapeutic strategies to specific niches, thereby minimizing potential side effects. Here, we discuss challenges and perspectives for niche-specific Treg targeting, which holds promise for highly efficient and precise medical interventions to combat metabolic disease.

Wnt10b is one of critical Wnt family members that being involved in networks controlling stemness, pluripotency and cell fate decisions. However, its role in adipose-resident T lymphocytes and further in fat metabolism yet remains largely unknown.

In the present study, we demonstrated a distinctive effect for Wnt10b on the relative balance of T lymphocytes in adipose tissue by using a Wnt10b knockdown mouse model. Wnt10b knockdown led to a reduction of adipose-resident CD4+ T cells and an elevation of Foxp3+/CD4+ Treg cells. Wnt10b-knockdown mice fed with standard diet showed less white fat deposition owing to the suppressed adipogenic process. Moreover, under high fat diet conditions, Wnt10b knockdown resulted in an alleviated obesity symptoms, as well as an improvement of glucose homeostasis and hepatic steatosis.

Collectively, we reveal an unexpected and novel function for Wnt10b in mediating the frequency of adipose-resident T cell subsets, that when knockdown skewing toward a Treg-dominated phenotype and further improving fat metabolism.

Immune cells, such as macrophages, B cells, neutrophils and T cell subsets, have been implicated in the context of obesity. However, the specific role of Th2 cells in adipose tissue function has remained elusive. Eight-week-old male CD3ε─/─ mice were randomly divided into two groups (≥ 5 mice per group): one received intravenous injection of Th2 cells isolated from LATY136F mice, while the other receiving PBS as a control. Both of groups were subjected to a high-fat diet (HFD). The adoptive transfer of polarized Th2 cells led to a significant reduction in obesity following a HFD. This reduction was accompanied by improvements in hepatic steatosis, glucose intolerance, and insulin resistance. Mechanistically, Th2 cell treatment promoted oxidative phosphorylation of adipocytes, thereby contributing to a reduction of lipid droplet accumulation. These findings suggest that Th2 cell therapy represents a novel approach for treating diet-induced obesity and other diseases involving lipid droplet accumulation disorders.

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, has no definite treatment so far. In fact, a combination of metabolic, hemodynamic, and immunological factors are involved in the pathogenesis of DN; therefore, effective disease management requires a holistic approach to all predisposing contributors. Due to the recent findings about the role of inflammation in the initiation and progression of kidney injury in diabetic patients and considerable advances in immunotherapy methods, it might be useful to revise and reconsider the current knowledge of the potential of immunomodulation in preventing and attenuating DN. In this review, we have summarized the findings of add-on therapeutic methods that have concentrated on regulating inflammatory responses in diabetic nephropathy, including phosphodiesterase inhibitors, nuclear factor-kB inhibitors, Janus kinase inhibitors, chemokine inhibitors, anti-cytokine antibodies, cell therapy, and vaccination.

All cells of the immune system reside in adipose tissue (AT), and increasing type 2 immune cells may be a therapeutic strategy to improve metabolic health. In our previous study using i.p. IL-5 injections to increase eosinophils, we observed that a standard vehicle control of 0.1% BSA also elicited profound AT eosinophilia. In this study, we aimed to determine whether BSA-induced AT eosinophilia results in metabolic benefits in murine models of diet-induced obesity. I.p. 0.1% BSA injections increased AT eosinophils after 4 wk. Despite elevating eosinophils to >50% of immune cells in the AT, body weight and glucose tolerance were not different between groups. Interestingly, BSA elicited epithelial IL-33 production, as well as gene expression for type 2 cytokines and IgE production that were dependent on IL-33. Moreover, multiple models of OVA sensitization also drove AT eosinophilia. Following transplantation of a donor fat pad with BSA-induced eosinophilia, OVA-sensitized recipient mice had higher numbers of bronchoalveolar lavage eosinophils that were recipient derived. Interestingly, lungs of recipient mice contained eosinophils, macrophages, and CD8 T cells from the donor AT. These trafficked similarly from BSA- and non-BSA-treated AT, suggesting even otherwise healthy AT serves as a reservoir of immune cells capable of migrating to the lungs. In conclusion, our studies suggest that i.p. injections of BSA and OVA induce an allergic response in the AT that elicits eosinophil recruitment, which may be an important consideration for those using OVA in animal models of allergic disease.

Regulatory T cells (Treg) are known to be critical for the maintenance of immune homeostasis by suppressing the activation of auto- or allo-reactive effector T cells through a diverse repertoire of molecular mechanisms. Accordingly, therapeutic strategies aimed at enhancing Treg numbers or potency in the setting of autoimmunity and allogeneic transplants have been energetically pursued and are beginning to yield some encouraging outcomes in early phase clinical trials. Less well recognized from a translational perspective, however, has been the mounting body of evidence that Treg directly modulate most aspects of innate immune response under a range of different acute and chronic disease conditions. Recognizing this aspect of Treg immune modulatory function provides a bridge for the application of Treg-based therapies to common medical conditions in which organ and tissue damage is mediated primarily by inflammation involving myeloid cells (mononuclear phagocytes, granulocytes) and innate lymphocytes (NK cells, NKT cells, γδ T cells and ILCs). In this review, we comprehensively summarize pre-clinical and human research that has revealed diverse modulatory effects of Treg and specific Treg subpopulations on the range of innate immune cell types. In each case, we emphasize the key mechanistic insights and the evidence that Treg interactions with innate immune effectors can have significant impacts on disease severity or treatment. Finally, we discuss the opportunities and challenges that exist for the application of Treg-based therapeutic interventions to three globally impactful, inflammatory conditions: type 2 diabetes and its end-organ complications, ischemia reperfusion injury and atherosclerosis.