BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway

Abstract

Inappropriate activation of the IL-23 signaling pathway causes chronic inflammation through the induction of immunopathological T h 17 cells in several tissues including the intestine, whereas adequate T h 17 responses are essential for host defense against harmful organisms. In the intestinal lamina propria, IL-23 is primarily produced by innate myeloid cells including dendritic cells (DCs) and macrophages (Mϕs). However, the molecular mechanisms underlying the regulation of IL-23 production by these cells remains poorly understood. In this study, we demonstrated that BATF2 regulates intestinal homeostasis by inhibiting IL-23-driven T-cell responses. Batf2 was highly expressed in intestinal innate myeloid subsets, such as monocytes, CD11b + CD64 + Mϕs and CD103 + DCs. Batf2 −/− mice spontaneously developed colitis and ileitis with altered microbiota composition. In this context, IL-23, but not TNF-α and IL-10, was produced in high quantities by intestinal CD11b + CD64 + Mϕs from Batf2 −/− mice compared with wild-type mice. Moreover, increased numbers of IFN-γ + , IL-17 + and IFN-γ + IL-17 + CD4 + T cells, but not IL-10 + CD4 + T cells, accumulated in the colons and small intestines of Batf2 −/− mice. In addition, RORγt-expressing innate lymphoid cells were increased in Batf2 −/− mice. Batf2 −/− Rag2 −/− mice showed a reduction in intestinal inflammation present in Batf2 −/− mice. Furthermore, the high numbers of intestinal IL-17 + and IFN-γ + IL-17 + CD4 + T cells were markedly reduced in Batf2 −/− mice when introducing Il23a deficiency, which was associated with the abrogation of intestinal inflammation. These results indicated that BATF2 in innate myeloid cells is a key molecule for the suppression of IL-23/IL-17 pathway-mediated adaptive intestinal pathology.

m6A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling

“…h Proposed mechanism scheme of BATF2 in GC. The m 6 A modification of BATF2 mRNA by METTL3 represses its expression; BATF2 promotes the expression of p53 by suppressing its ubiquitination and degradation, which further decreased ERK signaling Accumulating evidence has shown that BATF2 plays an important role in cell cycle regulation, EMT, inflammatory responses, and resistance to therapies [7,16,17]. In accordance with previous studies, we found that BATF2 acts as a multifunctional protein that inhibits GC growth and metastasis both in vitro and in vivo.…”

“…Accumulating evidence has shown that BATF2 plays an important role in cell cycle regulation, EMT, inflammatory responses, and resistance to therapies [ 7 , 16 , 17 ]. In accordance with previous studies, we found that BATF2 acts as a multifunctional protein that inhibits GC growth and metastasis both in vitro and in vivo.…”

SARI prevents ocular angiogenesis and inflammation in mice

“…During T cruzi infection, SARI functions as a negative regulator of IL‐23a in innate immune cells . We and a previous study by Kayama also demonstrated the protective role of SARI in colitis through regulating macrophage infiltration …”

Batf-mediated Epigenetic Control of Effector CD8+ T Cell Differentiation

“…Focusing on the gene expression data, we found that different combinations of the four TFs led to increased expression of several genes involved in the regulation of T cell homeostasis, activation, proliferation, differentiation and function (Figure 4A ), such as IRF family members ( Irf1 , Irf2 , Irf5 , Irf7 and Irf9 (Hammami et al, 2015; Hida et al, 2000; Martinet et al, 2015; Simon et al, 1997; Zhou et al, 2012)), JAK-STAT signaling pathway members ( Jak1 , Jak2 , Stat1 , Stat2 and Stat5a (Seif et al, 2017)), SOCS family members ( Socs1 , Socs2 and Socs4 (Palmer and Restifo, 2009) ), cytokine signaling ( Tgfb1 , Il2rb , Ifngr1 and Il17ra (Curtsinger et al, 2012; Oh and Li, 2013; Ross and Cantrell, 2018; Tosello Boari et al, 2018)) and other factors ( Atf3 , Batf2 , Ets2 , Gadd45a , Klf4 , etc. (Filén et al, 2010; Kayama et al, 2019; Salvador et al, 2005; Yamada et al, 2009; Zaldumbide et al, 2002)). To more systematically evaluate these transcriptional effects, we created a gene signature consisting of genes that are the most differentially expressed (up or down) between untreated fibroblasts and CD8+ T cells (using DESeq2; see Methods ).…”