DAP12 Expression in Lung Macrophages Mediates Ischemia/Reperfusion Injury by Promoting Neutrophil Extravasation

Abstract

Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell-membrane associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia-reperfusion injury, we took advantage of a clinically relevant mouse model of transplant-mediated lung ischemia reperfusion injury. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient deficiency in DAP12 protected against pulmonary ischemia reperfusion injury. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking.

Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling

“…For example, work from our group and others has demonstrated that alveolar macrophages contribute to pulmonary injury in the setting of sterile inflammation (16, 17). Alternatively, microglia plays a protective role after brain injury by modulating synapses (18).…”

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation

“…The bulk of our understanding of this relationship has come from experimental lung injury models showing that the initial recruitment of neutrophils was triggered by DAMP release. 34–37 As suggested by the “Danger Hypothesis” noted earlier, DAMPs stimulated cognate PRRs to induce the expression of ELR + CXC chemokines and IL-1β, both of which were found to promote expression of adhesion molecules on the luminal surface of vascular endothelium to stimulate neutrophil transendothelial migration into interstitial tissues. 38 In particular, early expression of IL-17, 39 a well-established stimulator of ELR + CXC chemokines, 40 may play a critical role in early neutrophil graft sequestration.…”

Role of monocytes and macrophages in regulating immune response following lung transplantation

“…Both IRI and PGD are characterized by early neutrophil infiltration of the alveolar spaces and recent studies have shown that this leads to the formation of neutrophil extracellular traps (NETs) and lung injury (33). Indeed, macrophage-induced early reperfusion injury and neutrophil recruitment has been postulated and verified by several groups using animal models of both warm and cold ischemia (53–57), but there is some conflicting evidence as to whether depletion of alveolar macrophages is protective or injurious (58). …”