EGFR regulates macrophage activation and function in bacterial infection.

Hardbower DM, Singh K, Asim M, Verriere TG, Olivares-Villagómez D, Barry DP, Allaman MM, Washington MK, Peek RM, Piazuelo MB, Wilson KT
J Clin Invest. 2016 126 (9): 3296-312

PMID: 27482886 · PMCID: PMC5004944 · DOI:10.1172/JCI83585

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.

MeSH Terms (21)

Animals Bacterial Infections Chemokines Citrobacter rodentium Cytokines Disease Progression ErbB Receptors Female Gastric Mucosa Helicobacter Infections Helicobacter pylori Humans Inflammation Macrophage Activation Macrophages Male Mice Mice, Transgenic NF-kappa B Phosphorylation Signal Transduction

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