Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes

Abstract

The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4(+) T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.

What goes around comes around: novel pharmacological targets in the gut–brain axis

“…This was verified in ob/ob, db/db and diet-induced models of obesity [Wang et al 2014]. Also, obese mice and mice deficient in IL-22 receptor had metabolic disorders such as insulin resistance and hyperglycemia, and were more susceptible to infection by the intestinal pathogen Citrobacter rodentium.…”

“…Also, obese mice and mice deficient in IL-22 receptor had metabolic disorders such as insulin resistance and hyperglycemia, and were more susceptible to infection by the intestinal pathogen Citrobacter rodentium. Administration of exogenous IL-22 normalized metabolic, endocrine and immune alterations and reduced intestinal inflammation [Wang et al 2014].…”

Cytokine signaling regulating adipose stromal cell trafficking

“…45 IL-22 is an important effector of lymphoid cells, whose signaling on epithelial cells through its receptor composed of IL-10R2 and IL-22R subunits has been implicated in chronic inflammatory diseases and cancer. 46 Although IL-22 signaling can be down-regulated in obesity upon immune system challenge, 47 IL-22 circulation is typically increased in obese humans. 45 Interestingly, ectopic expression of IL-22 in WAT leads to spontaneous liposarcoma formation in DIO mice.…”

All pain, no gain: Tc17 phantoms in GVHD

“…3 The story is further complicated by the fact that excess IL-17 can decrease the production of IL-22, disturbing gastrointestinal barrier function, which can be reversed with endogenous IL-22. 4 The IL-17/IL-22 axis also induces regenerative 3 a, a Paneth cell protein that is a validated biomarker of gastrointestinal GVHD. 5 Thus, IL-17 after BMT is key to the reconstitution of mucosal immunity and the restoration of normal barrier function after BMT, but in excess, it is primarily inflammatory, even for short periods, and can cause severe gastrointestinal damage.…”