Histone demethylase JMJD1A protects mice from enteric bacterial infection by upregulating CCL8 expression to recruit macrophages and CD4+ T cells

Abstract

Jumonji domain-containing 1A (JMJD1A, also known as KDM3A) is a histone demethylase that specifically demethylates H3K9me1/2 to enhance gene expression. The roles of JMJD1A in many physiological and pathological processes have been revealed. However, it is unclear whether JMJD1A is involved in host defense against enteric pathogen infection. In this study, we found that enteric infection with C. rodentium induced JMJD1A expression in colonic epithelial cells at the transcriptional level partly mediated by IRF1. After C. rodentium infection, JMJD1A-/- mice exhibited increased mortality, colonic injury, and C. rodentium load and systemic spread, suggesting that JMJD1A protects host against C. rodentium infection by enhancing C. rodentium clearance. JMJD1A-/- mice exhibited an impaired colonic recruitment of macrophages and CD4+ T cells as well as a reduced production of C. rodentium-specific IgG, leading to impaired clearance of C. rodentium. Reduced induction of a chemoattractant CCL8 in the colon of JMJD1A-/- mouse was responsible for reduced recruitment of macrophages and CD4+ T cells to the colon after C. rodentium infection. Mechanistically, JMJD1A cooperated with STAT1 and demethylated H3K9me2 on IRF1 promoter to promote the expression of IRF1, which can enhance CCL8 expression. Furthermore, JMJD1A cooperated with IRF1 and demethylated H3K9me2 on CCL8 promoter to induce CCL8 expression. Collectively, our study suggests that JMJD1A contributes to host defense against enteric bacteria, at least in part, by promoting CCL8 expression to enhance the recruitment of macrophages and CD4+ T cells.