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

## TL;DR

This study shows that the histone demethylase JMJD1A helps protect mice from gut bacterial infections by boosting CCL8, which attracts immune cells to fight the infection.

## Contribution

The study reveals a novel role of JMJD1A in host defense against enteric bacterial infection through CCL8 upregulation.

## Key findings

- JMJD1A-/- mice showed increased mortality and colonic injury after C. rodentium infection.
- CCL8 expression was reduced in JMJD1A-/- mice, impairing macrophage and CD4+ T cell recruitment.
- JMJD1A promotes CCL8 expression by demethylating H3K9me2 on its promoter in collaboration with IRF1.

## 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.

Bacterial enteritis is one of the most profound global public health challenges and serves as a significant contributor to child mortality in developing countries. And a mouse model infected with C. rodentium is wildly used to mimic bacterial enteritis in clinical settings. Therefore, an in-depth study of host-pathogen interactions and host defense mechanisms during bacterial enteritis pathogenesis will facilitate the development of preventive and therapeutic strategies against this disease. Here, we found that JMJD1A-/- mice exhibited increased C. rodentium load, mortality, colonic injury, and systemic spread compared to wild-type mice, suggesting the protective role of JMJD1A in host defense against enteric bacteria. Furthermore, IRF1 expression was dramatically increased in the colons, colonic epithelial cells, and CT26 cells, which was required for CCL8 induction for recruitment of macrophages and T cells after C. rodentium infection. Mechanistically, JMJD1A can cooperate with IRF1 to enhance the CCL8 promoter activity, and JMJD1A also cooperated with STAT1 to promote the expression of IRF1. In summary, JMJD1A played protective role to be cooperating with IRF1 and demethylated H3K9me2 on CCL8 promoter to induce CCL8 expression, which increased recruitment of macrophages and CD4+ T cells to the colon after C. rodentium infection. These results can provide new strategy for prevention and therapy of bacterial enteritis.