Excess Salt Intake Activates IL-21-Dominant Autoimmune Diabetogenesis via a Salt-Regulated Ste20-Related Proline/Alanine-Rich Kinase in CD4 T Cells.

The fundamental mechanisms by which a diet affects susceptibility to or modifies autoimmune diseases are poorly understood. Excess dietary salt intake acts as a risk factor for autoimmune diseases; however, little information exists on the impact of salt intake on type 1 diabetes. To elucidate the potential effect of high salt intake on autoimmune diabetes, nonobese diabetic (NOD) mice were fed a high-salt diet (HSD) or a normal-salt diet (NSD) from 6 to 12 weeks of age and monitored for diabetes development. Our results revealed that the HSD accelerated diabetes progression with more severe insulitis in NOD mice in a CD4+ T-cell-autonomous manner when compared with the NSD group. Moreover, expression of IL-21 and SPAK in splenic CD4+ T cells from HSD-fed mice was significantly upregulated. Accordingly, we generated T-cell-specific SPAK knockout (CKO) NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK CKO mice when compared with HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T-cell pathogenicity. Finally, pharmacological inhibition of SPAK activity using a specific SPAK inhibitor (closantel) in NOD mice ameliorated diabetogenesis, further illuminating the potential of a SPAK-targeting immunotherapeutic approach for autoimmune diabetes. Here, we illustrate that a substantial association between salt sensitivity and the functional impact of SPAK on T-cell pathogenicity is a central player linking high-salt-intake influences to immunopathophysiology of diabetogenesis in NOD mice.

Blimp-1 molds the epigenetic architecture of IL-21-mediated autoimmune diseases through an autoregulatory circuit.

Positive regulatory domain 1 (PRDM1) encodes B lymphocyte-induced maturation protein 1 (BLIMP1), also known as a master regulator of T cell homeostasis. We observed a negative relationship between Blimp-1 and IL-21 based on our previous data that Blimp-1 overexpression in T cells suppresses autoimmune diabetes while Blimp-1-deficient T cells contribute to colitis in NOD mice. Reanalysis of published data sets also revealed an inverse correlation between PRDM1 and IL21 in Crohn's disease. Here, we illustrate that Blimp-1 repressed IL-21 by reducing chromatin accessibility and evicting an IL-21 activator, c-Maf, from the Il21 promoter. Moreover, Blimp-1 overexpression-mediated reduction in permissive chromatin structures at the Il21 promoter could override IL-21-accelerated autoimmune diabetogenesis in small ubiquitin-like modifier-defective c-Maf-transgenic mice. An autoregulatory feedback loop to harness IL-21 expression was unveiled by the evidence that IL-21 addition induced time-dependent Blimp-1 expression and subsequently enriched its binding to the Il21 promoter to suppress IL-21 overproduction. Furthermore, intervention of this feedback loop by IL-21 blockade, with IL-21R.Fc administration or IL-21 receptor deletion, attenuated Blimp-1 deficiency-mediated colitis and reinforced the circuit between Blimp-1 and IL-21 in the regulation of autoimmunity. We highlight the translation of Blimp-1-based epigenetic and transcriptomic profiles applicable to a personalized medicine approach in autoimmune diseases.

Gut Microbiota-Modulated Metabolomic Profiling Shapes the Etiology and Pathogenesis of Autoimmune Diseases.

Autoimmunity is a complex and multifaceted process that contributes to widespread functional decline that affects multiple organs and tissues. The pandemic of autoimmune diseases, which are a global health concern, augments in both the prevalence and incidence of autoimmune diseases, including type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. The development of autoimmune diseases is phenotypically associated with gut microbiota-modulated features at the molecular and cellular levels. The etiology and pathogenesis of autoimmune diseases comprise the alterations of immune systems with the innate and adaptive immune cell infiltration into specific organs and the augmented production of proinflammatory cytokines stimulated by commensal microbiota. However, the relative importance and mechanistic interrelationships between the gut microbial community and the immune system during progression of autoimmune diseases are still not well understood. In this review, we describe studies on the profiling of gut microbial signatures for the modulation of immunological homeostasis in multiple inflammatory diseases, elucidate their critical roles in the etiology and pathogenesis of autoimmune diseases, and discuss the implications of these findings for these disorders. Targeting intestinal microbiome and its metabolomic associations with the phenotype of autoimmunity will enable the progress of developing new therapeutic strategies to counteract microorganism-related immune dysfunction in these autoimmune diseases.

Adipokine-Modulated Immunological Homeostasis Shapes the Pathophysiology of Inflammatory Bowel Disease.

Inflammatory colon diseases, which are a global health concern, include a variety of gastrointestinal tract disorders, such as inflammatory bowel disease and colon cancer. The pathogenesis of these colon disorders involves immune alterations with the pronounced infiltration of innate and adaptive immune cells into the intestines and the augmented expression of mucosal pro-inflammatory cytokines stimulated by commensal microbiota. Epidemiological studies during the past half century have shown that the proportion of obese people in a population is associated with the incidence and pathogenesis of gastrointestinal tract disorders. The advancement of understanding of the immunological basis of colon disease has shown that adipocyte-derived biologically active substances (adipokines) modulate the role of innate and adaptive immune cells in the progress of intestinal inflammation. The biomedical significance in immunological homeostasis of adipokines, including adiponectin, leptin, apelin and resistin, is clear. In this review, we highlight the existing literature on the effect and contribution of adipokines to the regulation of immunological homeostasis in inflammatory colon diseases and discuss their crucial roles in disease etiology and pathogenesis, as well as the implications of these results for new therapies in these disorders.