EGFR regulates macrophage activation and function in bacterial infection

Abstract

EGFR signaling regulates macrophage function, but its role in bacterial infection has not been investigated. Here, we assessed the role of macrophage EGFR signaling during infection with Helicobacter pylori, a bacterial pathogen that causes persistent inflammation and gastric cancer. EGFR was phosphorylated in murine and human macrophages during H. pylori infection. In human gastric tissues, elevated levels of phosphorylated EGFR were observed throughout the histologic cascade from gastritis to carcinoma. Deleting Egfr in myeloid cells attenuated gastritis and increased H. pylori burden in infected mice. EGFR deficiency also led to a global defect in macrophage activation that was associated with decreased cytokine, chemokine, and NO production. We observed similar alterations in macrophage activation and disease phenotype in the Citrobacter rodentium model of murine infectious colitis. Mechanistically, EGFR signaling activated NF-κB and MAPK1/3 pathways to induce cytokine production and macrophage activation. Although deletion of Egfr had no effect on DC function, EGFR-deficient macrophages displayed impaired Th1 and Th17 adaptive immune responses to H. pylori, which contributed to decreased chronic inflammation in infected mice. Together, these results indicate that EGFR signaling is central to macrophage function in response to enteric bacterial pathogens and is a potential therapeutic target for infection-induced inflammation and associated carcinogenesis.

Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications

“…S3B). The maintenance of the Lyz2 deletion and of high Cre expression during acute and chronic infection confirms the durability of the Odc deletion over time (14).…”

“…As macrophages are known to have a critical role in H. pylori-mediated gastritis (14,37) and C. rodentium colitis (14), we sought to interrogate the specific role of ODC in macrophages during these enteric infections, using a myeloid/macrophage-specific Odc knockout mouse.…”

“…An essential step in the responses to pathogens is macrophage activation. Macrophages have the capacity to alter cytokine/chemokine production and various other functions along the spectrum of M1 or M2 activation based on the stimulus detected (12)(13)(14). M1 macrophages represent a highly proinflammatory and antimicrobial subset of macrophages (12)(13)(14).…”

“…Macrophages have the capacity to alter cytokine/chemokine production and various other functions along the spectrum of M1 or M2 activation based on the stimulus detected (12)(13)(14). M1 macrophages represent a highly proinflammatory and antimicrobial subset of macrophages (12)(13)(14). M2 macrophages have various roles in wound repair, antiparasitic responses, control of inflammation, and have been implicated in tumor development and growth (15)(16)(17)(18).…”

“…H. pylori establishes a chronic infection in humans, which can be recapitulated in mice (14), marked by continuous, low-grade inflammation and host tolerance of the pathogen (31)(32)(33)(34). We also used the Citrobacter rodentium infectious colitis model (26,35).…”