The role of tissue resident cells in neutrophil recruitment

Abstract

Neutrophils are first responders of the immune system, rapidly migrating into affected tissues in response to injury or infection. To effectively call in this first line of defense, strategically placed cells within the vasculature and tissue respond to noxious stimuli by sending out coordinated signals that recruit neutrophils. Regulation of organ-specific neutrophil entry occurs at two levels. First, the vasculature supplying the organ provides cues for neutrophil egress out of the bloodstream in a manner dependent upon its unique cellular composition and architectural features. Second, resident immune cells and stromal cells within the organ send coordinated signals that guide neutrophils to their final destination. Here, we review recent findings that highlight the importance of these tissue-specific responses in the regulation of neutrophil recruitment and the initiation and resolution of inflammation.

Figure 1. Tissue-resident cellular players in neutrophil extravasation through the vessel wall into tissues

Regulation of tissue-specific neutrophil recruitment into organs occurs at two levels. Level 1 consists of the vasculature supplying the organ. First, endothelial cells induce neutrophil rolling (1) through selectin expression and next induce neutrophil arrest (2) through chemokine-induced activation of integrins. It should be noted that the cell surface receptors required for these processes differ depending upon the organ the blood vessel is supplying. Neutrophils then transmigrate (3) through the endothelial cell layer into the abluminal space. Pericytes encase the abluminal side of capillaries and post-capillary venules. Upon stimulation by TLR ligands or cytokines, pericytes promote neutrophil recruitment by producing neutrophil-active chemokines and upregulating surface ICAM-1, enabling neutrophils to crawl on their surfaces in the abluminal space (4) towards basement membrane low-expression regions (LER). In addition, upon activation pericytes undergo shape change and contract, enlarging areas of exposed basement membrane and available space for neutrophils to pass through. Perivascular macrophages exist in close contact with pericytes and express toll-like receptors and lectins that enable them to produce neutrophil-active chemokines upon stimulation. Perivascular mast cells contain preformed TNF and neutrophil-active chemokines in their granules, which may be rapidly released upon stimulation with immune complexes or TLRs. The distribution of perivascular cells is site- and organ-specific. Level 2 consists of the nature of the tissue resident cells that provide further guidance for neutrophils (5) into the interstitium and in some tissues across the epithelium. Macrophages and immune cells produce cytokines that activate resident tissue fibroblasts and epithelial cells to produce neutrophil-active chemokines. Previously recruited monocytes may also differentiate into tissue macrophages, secreting cytokines and chemokines that further influence neutrophil recruitment.

Figure 2. Tissue resident cells coordinate neutrophil recruitment through epithelial cell layers

Resident Ly6C− macrophages sense infection by E. coli (1) and produce MIF and CXCL1 (2), which recruit monocytes (3) and neutrophils (4), respectively, from the circulation into the interstitial space of the bladder. Newly recruited Ly6C+ monocytes release TNF (5), which induces Ly6C− macrophages to release CXCL2 (6). CXCL2 stimulates neutrophils to produce MMP9 (7), which enables them to cross the uroepithelium and reach the bladder lumen to control infection from invading pathogens.