EGFR regulates macrophage activation and function in bacterial infection
Dana M. Hardbower, … , M. Blanca Piazuelo, Keith T. Wilson
Dana M. Hardbower, … , M. Blanca Piazuelo, Keith T. Wilson
Published August 2, 2016
Citation Information: J Clin Invest. 2016;126(9):3296-3312. https://doi.org/10.1172/JCI83585.
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Research Article Gastroenterology

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.

Authors

Dana M. Hardbower, Kshipra Singh, Mohammad Asim, Thomas G. Verriere, Danyvid Olivares-Villagómez, Daniel P. Barry, Margaret M. Allaman, M. Kay Washington, Richard M. Peek Jr., M. Blanca Piazuelo, Keith T. Wilson

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Figure 1

Increased p-EGFR levels in human Gmacs in H. pylori–induced gastritis and precancerous intestinal metaplasia.

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Increased p-EGFR levels in human Gmacs in H. pylori–induced gastritis an...
(A) Representative immunofluorescence images of human gastric biopsies with normal histology and active, nonatrophic gastritis. CD68 = red, EGFR p-Y1068 = green; merge = yellow; DAPI = blue. n = 4 normal samples and 5 gastritis samples. Scale bars: 50 μM. (B) Quantification of the percentage of CD68+p-EGFR+ macrophages among the total number of CD68+ cells in 10 fields per slide from images shown in A. The slides were analyzed in a blinded manner. n = 4 normal samples and 5 gastritis samples. ***P < 0.001, by 2-tailed Student’s t test. (C) Representative H&E-stained images and immunofluorescence images of gastric tissues from the Vanderbilt University TMA. CD68 = red; EGFR p-Y1068 = green; merge = yellow; DAPI = blue. n = 12 normal samples, 41 gastritis samples, and 9 intestinal metaplasia samples. Scale bars: 100 μM. (D) Quantification of the percentage of CD68+p-EGFR+ cells among the total number of cells in each individual core in the TMA, as determined by CellProfiler. n = 12 normal samples, 41 gastritis samples, and 9 intestinal metaplasia samples. *P < 0.05 and **P < 0.01, by 1-way ANOVA with the Kruskal-Wallis test, followed by the Mann-Whitney U test.