Piezo1 mediates abnormal type 2 immune response to aggravate ischemia–reperfusion acute lung injury which by regulating alveolar macrophages derived IL-33: A hypothesis

Abstract

The pathogenesis of ischemia–reperfusion acute lung injury (IR-ALI) is not yet fully understood. We previously reported that unwonted increased type 2 immunity plays a key role in the pathogenesis and the pathophysiological process in acute haemorrhagic inducedlung injury. Progressive lung edema after ischemia reperfusion is accompanied by the change of lung cyclical hydrostatic force. The changed lung mechanical force could activate the mechanosensitive Piezo1 channel in alveolar macrophages. Furthermore, our group had elucidated that microenvironmental stiffness exacerbated hindlimb ischemia reperfusion injury by activating Piezo1 in bone marrow-derived macrophages. Considering early findings that IL-33 is a potent driver of pulmonary type 2 immunity, that Piezo1 plays an important role in regulating macrophages biological activity and that alveolar macrophages are involved in orchestrating the early abnormal detrimental type 2 inflammatory response in lung ischemia–reperfusion injury, we herein hypothesize that the change of mechanical force in lung after ischemia–reperfusion might activate Piezo1/IL-33/type 2 immunity axis and aggravate lung ischemic injury. Mechanistically, Piezo1 mediates extracellular Ca2+influx and activates Ca2+-dependent Calcineurin-NFAT signaling in alveolar macrophages, leading to transcriptional activation of IL-33, thereby promoting abnormal type 2 immune response and participating in the occurrence and development of IR-ALI. Future validation of these mechanisms could provide a deeper explanation of the new pathogenesis of IR-ALI and ultimately serve for clinical treatment.