Chlorination of epithelial tight junction proteins by neutrophil myeloperoxidase promotes barrier dysfunction and mucosal inflammation
Ian M. Cartwright, Liheng Zhou, Samuel D. Koch, Nichole Welch, Daniel Zakharov, Rosemary Callahan, Calen A. Steiner, Mark E. Gerich, Joseph C. Onyiah, Sean P. Colgan
Ian M. Cartwright, Liheng Zhou, Samuel D. Koch, Nichole Welch, Daniel Zakharov, Rosemary Callahan, Calen A. Steiner, Mark E. Gerich, Joseph C. Onyiah, Sean P. Colgan
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Research Article Inflammation

Chlorination of epithelial tight junction proteins by neutrophil myeloperoxidase promotes barrier dysfunction and mucosal inflammation

Abstract

Neutrophils (polymorphonuclear leukocytes, PMNs) comprise a major component of the immune cell infiltrate during acute mucosal inflammation and have an important role in molding the inflammatory tissue environment. While PMNs are essential to clearance of invading microbes, the major PMN antimicrobial enzyme myeloperoxidase (MPO) can also promote bystander tissue damage. We hypothesized that blocking MPO would attenuate acute colitis and prevent the development of chronic colitis by limiting bystander tissue damage. Using the acute and chronic dextran sodium sulfate model of murine colitis, we demonstrated that MPO-deficient mice experienced less inflammation and more rapidly resolved colitis relative to wild-type controls. Mechanistic studies demonstrated that activated MPO disrupted intestinal epithelial barrier function through the dysregulation of the epithelial tight junction proteins. Our findings revealed that activated MPO chlorinates tyrosine within several tight junction proteins, thereby promoting tight junction mislocalization and dysfunction. These observations in cell models and in murine colitis were validated in human intestinal biopsies from individuals with ulcerative colitis and revealed a strong correlation between disease severity (Mayo score) and tissue chlorinated tyrosine levels. In summary, these findings implicate MPO as a viable therapeutic target to limit bystander tissue damage and preserve mucosal barrier function during inflammation.

Authors

Ian M. Cartwright, Liheng Zhou, Samuel D. Koch, Nichole Welch, Daniel Zakharov, Rosemary Callahan, Calen A. Steiner, Mark E. Gerich, Joseph C. Onyiah, Sean P. Colgan

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Figure 2

MPO promotes chronic colitis.

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MPO promotes chronic colitis. (A) Percentage weight loss and (B) DAI fro...
(A) Percentage weight loss and (B) DAI from WT and MPO-KO mice that received 2.5% DSS in their drinking water for 5 days and were allowed to recover for 16 days before receiving additional rounds of 2.5% DSS for 5 days. Mice received 1, 2, or 3 rounds of 2.5% DSS. (C) Colon lengths from WT and MPO-KO mice collected after 2 or 3 rounds of 2.5% DSS. (D and E) MESO scale analysis of distal colon tissue collected 2 days after DSS was removed in WT and MPO-KO mice after 2 or 3 rounds of 2.5% DSS. The tissue was analyzed for KC/GRO, IL-6, TNF-α, and IFN-γ. (F) Histological score from distal colon tissue harvested at the end of 2 or 3 rounds of 2.5% DSS. (G) Representative microscopy (original magnification, ×10) images of hematoxylin and eosin–stained colon tissue after 2 or 3 rounds of 2.5% DSS. n = 6–14 mice per group (A–C, F, and G). n = 4 mice per group (D and E). Data are expressed as mean ± SD, and the P value was determined by t test (D and E), 1-way ANOVA (C and F), or 2-way ANOVA (A and B) where appropriate. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.