Neutrophils and the inflammatory tissue microenvironment in the mucosa

Abstract

The interaction of neutrophils (PMNs) and epithelial cells are requisite lines of communication during mucosal inflammatory responses. Consequences of such interactions often determine endpoint organ function, and for this reason, much interest has developed around defining the constituents of the tissue microenvironment of inflammatory lesions. Physiologic in vitro and in vivo models have aided in the discovery of components that define the basic inflammatory machinery that mold the inflammatory tissue microenvironment. Here, we will review the recent literature related to the contribution of PMNs to molding of the tissue microenvironment, with an emphasis on the gastrointestinal (GI) tract. We focus on endogenous pathways for promoting tissue homeostasis and the molecular determinants of neutrophil-epithelial cell interactions during ongoing inflammation. These recent studies highlight the dynamic nature of these pathways and lend insight into the complexity of treating mucosal inflammation.

Keywords: colitis; epithelium; hypoxia-inducible factor; inflammation; metabolism; mucosa; nucleoside; nucleotidase.

FIGURE 1. Neutrophil polarization in response to microenvironmental reprogramming

PMN respond to environmental cues to elicit differential polarization and function. Counter-clockwise from the top: 1) TAN-N1 migrate to tumor periphery, their nuclei exhibit a “hypersegmented” appearance and they mediate anti-tumoral activities. 2) TAN-N2 respond to tumor-derived TGF-β, their nuclei appear “circular” and they elicit pro-tumoral role. 3) Hybrid PMN/DC represent an immature PMN precursor exposed to GM-CSF and adopt a hybrid antimicrobial and antigen presenting phenotype. 4) Pro-angiogenic PMN may be derived from longer-lived mature PMN and respond specifically to sites of ischemia/hypoxia. 5) PMN isolated from MRSA-sensitive hosts secrete anti-inflammatory IL-10 and promote alternative activation in macrophages. 6) PMN isolated from MRSA-resistant hosts secrete IL-12 and influence classical activation in macrophages. TAN: tumor associated neutrophil; DC: dendritic cell; MRSA: methicillin-resistant Staphylococcus aureus.