期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 9, 页码 3296-3312出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI83585
关键词
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资金
- NIH [R01DK053620, R01AT004821, R01CA190612, P01CA116087, P01CA028842, T32GM008554, F31DK10715, P30DK058404, P30CA068485]
- Department of Veterans Affairs Merit Review grant [I01BX001453]
- Thomas F. Frist Sr. Endowment
- Vanderbilt Center for Mucosal Inflammation and Cancer
- Vanderbilt Digestive Disease Research Center - NIH [P30DK058404]
- Specialized Program of Research Excellence (SPORE) in GI Cancer - NIH [P50CA095103]
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-kappa B 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.
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