Activation of p38α in T Cells Regulates the Intestinal Host Defense against Attaching and Effacing Bacterial Infections

Abstract

Intestinal infections by attaching and effacing (A/E) bacterial pathogens cause severe colitis and bloody diarrhea. Although p38α in intestine epithelial cells (IEC) plays an important role in promoting protection against A/E bacteria by regulating T cell recruitment, its impact on immune responses remains unclear. In this study, we show that activation of p38α in T cells is critical for the clearance of the A/E pathogen Citrobacter rodentium. Mice deficient of p38α in T cells, but not in macrophages or dendritic cells, were impaired in clearing C. rodentium. Expression of inflammatory cytokines such as IFN-γ by p38α-deficient T cells was reduced, which further reduced the expression of inflammatory cytokines, chemokines and anti-microbial peptide by IECs and led to reduced infiltration of T cells into the infected colon. Administration of IFN-γ activated the mucosal immunity to C. rodentium infection by increasing the expression of inflammation genes and the recruitment of T cells to the site of infection. Thus, p38α contributes to host defense against A/E pathogen infection by regulating the expression of inflammatory cytokines that activate host defense pathways in IECs.

Tissue-Specific Regulation of p38α-Mediated Inflammation in Con A–Induced Acute Liver Damage

“…Induction of cytokine mRNA by ConA was significantly reduced in p38α-deficient leukocytes (Figure 4C). Consistently, our study also indicated that TCR-induced expression of cytokine genes was also significantly reduced in p38α-deficient T cells compared with control cells (21) (data not shown). However, induction of cytokine mRNA by α-GalCer did not differ between control and p38α-deficient leukocytes (Figure 4D), implying that p38α does not directly regulate the induction of inflammatory cytokine expression in NKT cells, but is involved in the post-transcriptional regulation of gene expression as shown previously (29).…”

“…Additionally, TUNEL assay indicated that induction of apoptosis was significantly reduced in the liver tissue of p38α ΔT mice (Figure 1D). Because T and NKT cells play an important role in ConA-induced liver damage (26-28), and Lck-cre-mediated deletion of p38α was observed in T cells as well as NKT cells of hepatic leukocytes (Supplemental Figure 1) (21,29), our results indicate that p38α promotes the activation of T and NKT cells in ConA-induced hepatitis.…”

“…First, we generated macrophage-, T cell-, or hepatocyte-specific p38α-deficient mouse strains, and confirmed deletion of p38α is specific in hepatocytes in albumin-cre-driven conditional knockout mice (6,21) (Supplemental Figure 1). Using ConA-induced acute liver injury model (24,25), we investigated the tissue-specific role of p38α in liver inflammation.…”

“…Macrophage-specific (LysMCre-p38α Δ/Δ ), or T lymphocyte-specific p38α deficient mice (LckCre-p38α Δ/Δ ) were generated previously (6,21). p38α floxed mice were crossed with liver-specific Cre-expressing mice (Alb-Cre, The Jackson Laboratory) to obtain a liver-specific p38α-deficient mouse strain.…”

“…RNAs from tissues or cells were prepared with Trizol reagent (Invitrogen), and qPCR was performed (21). …”