Polymorphonuclear leukocytes (PMN) play a crucial role in host protection, however, if not rapidly removed from sites of inflammation cause considerable tissue damage. We postulated that transmigrating PMN leave a """"""""transcriptional imprint"""""""" on the cells they migrate across. Our initial findings indicated that infiltrating neutropils (PMN) deplete oxygen to an extent sufficient to generate a hypoxic microenvironment during colitis. Initiation of this microenvironment was dependent on the PMN respiratory burst and resulted in HIF stabilization in surrounding epithelia. Guided by microarray analysis, we identified a number of cytokines regulated by PMN-epithelial crosstalk. These cytokines were regulated in a coordinated, time-dependent fashion and are known to influence the polarity of macrophages. Considering that macrophages are highly plastic cells, influenced by their microenvironment, we hypothesize that the polarity of infiltrating monocytes is influenced by factors secreted in response to PMN-epithelial crosstalk.
Three specific aims are directed at testing this hypothesis:
In Specific Aim 1, we will define the contribution of epithelial hypoxia inducible factor (HIF) to regulating macrophage polarity in vitro and during inflammation in vivo.
Specific Aim 2 is designed to elucidate the mechanism behind delayed production of STAT3-dependent anti-inflammatory cytokines in hypoxia.
In Specific Aim 3, we aim to ascertain the functional consequences of crosstalk between macrophages and epithelial HIF/STAT3-dependent factors on restitution of the epithelium.

Public Health Relevance

This proposal aims to gain insight into how an acute inflammatory event can establish a microenvironment to either coordinate the resolution of inflammation, or perpetuate it to generate a chronic inflammatory state. Macrophages are highly plastic cells influenced by their local environment that represent the fulcrum of inflammation, able to shift the balance of inflammation / resolution depending on their activation state. Results from the studies proposed herein will attempt to ascertain the mechanistic influence of epithelial-derived factors that regulate the microenvironment in which macrophages function and ultimately regulate inflammation / resolution.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Colgan, Sean P; Campbell, Eric L (2017) Oxygen metabolism and innate immune responses in the gut. J Appl Physiol (1985) 123:1321-1327
Kuhn, K A; Schulz, H M; Regner, E H et al. (2017) Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. Mucosal Immunol :
Zheng, Leon; Kelly, Caleb J; Battista, Kayla D et al. (2017) Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2. J Immunol 199:2976-2984
Hall, Caroline H T; Campbell, Eric L; Colgan, Sean P (2017) Neutrophils as Components of Mucosal Homeostasis. Cell Mol Gastroenterol Hepatol 4:329-337
Ehrentraut, Stefan F; Curtis, Valerie F; Wang, Ruth X et al. (2016) Perturbation of neddylation-dependent NF-?B responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation. Mol Biol Cell :
Colgan, Sean P; Campbell, Eric L; Kominsky, Douglas J (2016) Hypoxia and Mucosal Inflammation. Annu Rev Pathol 11:77-100
Campbell, Eric L; Kao, Daniel J; Colgan, Sean P (2016) Neutrophils and the inflammatory tissue microenvironment in the mucosa. Immunol Rev 273:112-20
Selfridge, Andrew C; Cavadas, Miguel A S; Scholz, Carsten C et al. (2016) Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia. J Biol Chem 291:11800-8
Curtis, Valerie F; Ehrentraut, Stefan F; Campbell, Eric L et al. (2015) Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses. FASEB J 29:208-15
Kelly, Caleb J; Zheng, Leon; Campbell, Eric L et al. (2015) Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe 17:662-71

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