Macrophage–endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa

Abstract

Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here, we describe what we believe to be a new mechanism where vessel-associated macrophages through localized interactions primed EC responses to form ICAM-1 “hot spots” to support PMN TEM. Using real-time intravital microscopy of LPS-inflamed intestines in CX3CR1-EGFP macrophage-reporter mice, complemented by whole-mount tissue imaging and flow cytometry, we found that macrophage vessel association is critical for the initiation of PMN-EC adhesive interactions, PMN TEM, and subsequent accumulation in the intestinal mucosa. Anti–colony stimulating factor 1 receptor Ab-mediated macrophage depletion in the lamina propria and at the vessel wall resulted in elimination of ICAM-1 hot spots impeding PMN-EC interactions and TEM. Mechanistically, the use of human clinical specimens, TNF-α–KO macrophage chimeras, TNF-α/TNF receptor (TNF-α/TNFR) neutralization, and multicellular macrophage-EC-PMN cocultures revealed that macrophage-derived TNF-α and EC TNFR2 axis mediated this regulatory mechanism and was required for PMN TEM. As such, our findings identified clinically relevant mechanisms by which macrophages regulate PMN trafficking in inflamed mucosa.

CNS resident macrophages enhance dysfunctional angiogenesis and circulating monocytes infiltration in brain arteriovenous malformation

“…Recent studies show that vascular-associated macrophages (VAM) promote highly localized ICAM1 expression in ECs initiating EC-neutrophil adhesive interactions. 27 Perivascular microglia could also physically contact with ECs and modulate the expression of tight junction protein claudin-5. 28 In this study, we showed an improvement of claudin-5 expression after a transient reduction of resident macrophages in bAVMs, which further indicates that the resident macrophages play roles in maintaining BBB integrity and priming inflammation in disease conditions.…”

A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism

“…Neutrophil and ECs interaction allows for unidirectional migration through venular walls ( 54 , 60 , 61 ). Most importantly, aberrant neutrophil-endothelial interactions are implicated in a wide range of inflammatory diseases that relate to neutrophil influx and tissue damage ( 62 – 64 ). Similarly, neutrophil-epithelial crosstalk is involved in the maintenance of the epithelial-lined organs where uncontrolled neutrophil processes contribute to pathogenesis of diseases ( 65 – 68 ).…”

Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism

“…As such, tumor EC-derived IL-6 induces alternative polarization and immunosuppressive phenotypes in perivascular macrophages [155]. In addition, Lyve-1 + macrophages have a critical role in creating a pro-angiogenic TME through maintaining and expanding a perivascular mesenchymal cell population, ultimately establishing a specialized niche that supports tumor progression [156]. Macrophage-derived TNF-α and endothelial TNF receptor are identified as crucial components of this regulatory mechanism.…”