Th22 cells promote the transition from homeostatic to reactive microglia in diabetic encephalopathy

Diabetic encephalopathy (DE) is one of the most serious complications of diabetes mellitus (DM), and its pathogenesis has not yet been clarified. Th22 cells are a newly discovered class of CD4⁺ T cells that play important roles in inflammatory, autoimmune and infectious diseases. However, it is unclear whether Th22 cells are involved in the pathogenesis of DE.

We established a T2DM mouse model in vivo and cocultured Th22 cells with microglia under high glucose (HG) conditions in vitro. Cognitive dysfunction was evaluated using the Morris water maze (MWM) test; blood‒brain barrier (BBB) integrity was evaluated using the Evans blue (EB) extravasation assay; Th22 cells and IL-22 receptors were detected by immunofluorescence; and IL-1β, TNF-α, iNOS, CD86, Arg-1, and CD206 protein expression was measured by Western Blot (WB) analysis.

Th22 cells passed through the BBB into the hippocampus and secreted interleukin-22 (IL-22), and the mice subsequently exhibited decreased learning and memory abilities. In the DE model, IL-22 promoted the transformation of homeostatic microglia into reactive microglia as well as the inflammatory response. Additionally, coculture of Th22 cells with BV2 microglia cultured under HG conditions increased the production of proinflammatory cytokines, and the microglia showed reactive changes. Mechanistically, IL-22Rα1 acted as a ligand, and IL-22 bound to IL-22Rα1 on microglia to drive primary microglia-induced inflammatory responses. Interestingly, interleukin-22 binding protein (IL-22BP) directly binds to IL-22Rα1 on microglia to inhibit the proinflammatory effects of IL-22.

Th22 cells secrete IL-22 after passing through the BBB into the hippocampus and promote the transformation of homeostatic microglia into reactive microglia, which induces an inflammatory response, exacerbates learning and memory impairment and cognitive deficits, and contributes to and accelerates the development of DE.