Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury

Abstract

Significance Intravital imaging, oxidative lipidomics, and a transplant model were used to define mechanisms that regulate neutrophil recruitment into lungs during ischemia reperfusion injury, a clinically relevant form of sterile inflammation. We found that early neutrophil-mediated damage is largely confined to the subpleural vasculature, a process that is orchestrated by a spatially restricted distribution of nonclassical monocytes that produce chemokines following necroptosis of pulmonary cells. Neutrophils disrupt the integrity of subpleural capillaries, which is associated with impaired lung function. Neutrophil-mediated vascular leakage is dependent on TLR4 expression on vascular endothelium, NOX4 signaling, and formation of neutrophil extracellular traps. Our research provides insights into mechanisms that regulate neutrophil recruitment during sterile lung inflammation and lays the foundation for developing new therapies.

IL-1β–dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction

“…We have previously reported that ischemia-reperfusion injury is inherent to lung transplantation and is dependent on the influx of host neutrophils into the transplanted lung through retained donor-origin pulmonary intravascular nonclassical monocytes ( 22 , 23 ). To determine whether LRAs can independently induce lung graft dysfunction, we used lungs from murine Nur77 –/– ( Nr4a1 –/– ) donors, which lack nonclassical monocytes and do not experience neutrophil-mediated ischemia-reperfusion injury, as we previously reported ( 23 ).…”

The role of extracellular traps in ischemia reperfusion injury

“…Using intravital imaging, oxidative lipidomics, and transplant models, Li et al (114) demonstrated that TLR4 signaling and downstream NOX4 expression in vascular endothelial cells during lung I/R mediate neutrophil recruitment to the lungs and increase NET formation. The knockdown of TLR4 expression in vascular endothelial cells results in decreased neutrophil infiltration and NETosis (114). Treatment with DNase I reduces lung neutrophil extravasation and subpleural NET formation, thus improving graft function (114).…”

“…( 114 ) demonstrated that TLR4 signaling and downstream NOX4 expression in vascular endothelial cells during lung I/R mediate neutrophil recruitment to the lungs and increase NET formation. The knockdown of TLR4 expression in vascular endothelial cells results in decreased neutrophil infiltration and NETosis ( 114 ). Treatment with DNase I reduces lung neutrophil extravasation and subpleural NET formation, thus improving graft function ( 114 ).…”

“…The knockdown of TLR4 expression in vascular endothelial cells results in decreased neutrophil infiltration and NETosis ( 114 ). Treatment with DNase I reduces lung neutrophil extravasation and subpleural NET formation, thus improving graft function ( 114 ). However, studies also show that although DNase I treatment can rapidly degrade NETs within the graft, the ensuing release of NET fragments promotes the production of inflammatory factors in human alveolar macrophages by activating the TLR-MyD88 signaling pathway ( 154 ).…”

The Role and Mechanism of the Vascular Endothelial Niche in Diseases: A Review

“…The critical function of chemokines is to manage the migration of hemameba to their specific position during equilibrium process when the process goes disease disorders. Chemokines directionally induce chemotaxis of nearby reactive cells through promoting proliferation of vascular endothelial cells and angiogenesis ( Li et al, 2022 ). Vascular endothelial cells, chemokine (C-X-C motif) ligand 12 (CXCL12)-rich reticular cells, and mesenchymal stromal cell-regulated chemokines, cytokines, and cell surface adhesion molecules have been identified as microenvironmental cells in neoplastic hematopoiesis ( Kaushansky and Zhan, 2018 ).…”