PMN-EPITHELIAL CROSSTALK COORDINATES MONOCYTE POLARIZATION DURING INFLAMMATION

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): 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.