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  • In autoimmune diseases lymphocytes penetrate

    2021-10-16

    In autoimmune diseases, lymphocytes penetrate into the inflammatory lesions of tissues, where it is prominently hypoxic or even anoxic, and utilize glycolysis for an energy supply after activation or under hypoxia (Sitkovsky and Lukashev, 2005; Palazon et al., 2014), which is modulated by the oxygensensing HIF transcription factors. HIFs are heterodimeric proteins of the basic helix-loop-helix family and consist of the oxygen-dependent α subunit and the constitutively expressed β subunit (Balamurugan, 2016). Under normal oxygen tensions, HIFα subunits are hydroxylated by prolyl hydroxylases and are subsequently subjected to oxygen-dependent proteasomal degradation mediated by the von Hippel–Lindau tumor-suppressor protein (VHL) (Ivan et al., 2001; Jaakkola et al., 2001). However, the HIFα subunit can stably translocate to the nucleus and dimerize with the HIF-1β subunit to drive the transcription of targets under hypoxic conditions (Cramer et al., 2003; Peyssonnaux et al., 2005). A large body of research has shown that HIF-1α triggers the transcription of many glycolytic genes and plays a vital role in innate and adaptive immune response (Brown and Taylor, 2018; Ratcliffe, 2007). HIF-1α increases macrophage aggregation, invasion, and motility and derives the expression of pro-inflammatory cytokines. In neutrophils, HIF-1α increases cell survival by inhibiting apoptosis and triggers NF-κB dependent neutrophilic inflammation (Walmsley et al., 2005). HIF-1α in dendritic fccp cells is necessary for the activation of Tregs to control intestinal inflammation (Fluck et al., 2016). HIF-1α increases the expression of RORγt, which in turn promotes IL-17 production and Th17 cell development and supports Treg cell function (Higashiyama et al., 2012). HIF-1α has also been reported to induce IL-12p40 to suppress mucosal Th1 and Th17 responses, which protects against colitis (Marks et al., 2017). Although HIF-1α has been widely studied in T cells and myeloid cells, its function in fccp is largely unexplored and was only known to contribute to IL-10 production by B cells (Meng et al., 2018). In the present study, we found that the expression of CD11b on B cells was systemically increased in the spleen and gut-associated lymphoid tissues (GALT) during the DSS-induced colitis process. Compared to WT cells, B cells from colitic mice had a greater expression of the transcriptional regulator HIF-1α. Knockdown or inhibition of HIF-1α led to the down-expression of CD11b in B cells in vitro. Furthermore, Rag-1−/− mice adoptively transferred with HIF-1α-knockdown B cells exhibited a severer colitic phenotype and has the decreased expression of CD11b in B cells than those transferred with WT B cells. The CD11b transcription was then identified to be regulated by a HIF-1α and p-STAT3 complex via binding onto the hypoxia-responsive element (HRE) regions of Itgam promoter, which was guaranteed by the MEK/ERK pathway activation and IL-10 secretion. Taken together, these findings reveal HIF-1α as a vital transcription factor for B cells expressing CD11b to exert a protective function in colitis.
    Results
    Discussion In this study, we first found that CD11b expression on B cells systemically increased in gut-associated lymphoid tissue and the spleen during the process of experimental colitis. B cells in colitis had a greater expression of the important transcription factor HIF-1α than naïve B cells from WT mice. We then demonstrated that HIF-1α knockdown by siRNA impaired the B cells’ protective activity in colitis in vivo and reduced the CD11b expression in B cells in vitro, and the HRE II and IV of four putative HRE regions in the Itgam promoter were responsible for HIF-1α binding to promote Itgam transcription. Finally, the MEK/ERK and STAT3 signaling pathways were shown to be involved in LPS- and colitis-induced CD11b upregulation. Our study indicates that the transcriptional complex of HIF-1α and p-STAT3 was activated by the MEK/ERK pathway and secreted IL-10, and consequently activated HRE regions of the Itgam promoter (Fig. 6).