Fig. 8. Schematic diagram of MANF ameliorating colitis.
The macrophages in colonic tissue are activated by invading microbes or DSS and produce cytokines, which stimulate macrophages to differentiate to CX3CR1int proinflammatory macrophages. On the other hand, MANF is upregulated in macrophages and transferred to the nuclei, where it inhibits CHOP expression during this process. Because CHOP positively regulates BATF2 transcription by binding to BATF2 promoter, the expression of BATF2 downstream genes, including the inflammatory chemokines (CXCL9, CXCL10, CXCL11) and proinflammatory cytokines (TNF-α, IL-1β, IL-12p40) was enhanced, which results in Th17 cells activation and intestinal epithelial cells apoptosis. Consequently, MANF ameliorates colitis and repairs intestinal injury via inhibiting CHOP-BATF2 signaling.