PTRF-IL33-ZBP1 signaling mediating macrophage necroptosis contributes to HDM-induced airway inflammation

Abstract

Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding protein 1 (ZBP1)-sensing Z-RNAs induces necroptosis which causes inflammatory diseases. House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. Whether PTRF via IL-33 and ZBP1 mediates HDM-induced macrophage necroptosis and airway inflammation remains unclear. Here, we found that deficiency of PTRF could reduce lung IL-33, ZBP1, phosphor-receptor-interacting protein kinase 3 (p-RIPK3), and phosphor-mixed lineage kinase domain-like (p-MLKL) (necroptosis executioner), and airway inflammation in an HDM-induced asthma mouse model. In HDM-treated macrophages, ZBP1, p-RIPK3, and p-MLKL levels were markedly increased, and these changes were reversed by deletion of Cavin-1. Deletion of Il33 also reduced expression of ZBP1, p-RIPK3, and p-MLKL in HDM-challenged lungs. Moreover, IL-33 synergizing with HDM boosted expression of ZBP1, p-RIPK3, and p-MLKL in macrophages. In bronchial epithelial cells rather than macrophages and vascular endothelial cells, PTRF positively regulates IL-33 expression. Therefore, we conclude that PTRF mediates HDM-induced macrophage ZBP1/necroptosis and airway inflammation, and this effect could be boosted by bronchial epithelial cell-derived IL-33. Our findings suggest that PTRF-IL33-ZBP1 signaling pathway might be a promising target for dampening airway inflammation.

Necroptosis plays a role in TL1A-induced airway inflammation and barrier damage in asthma

“…In addition, recent studies have shown that the MLKL inhibitor GW806742X can block IL-33 secretion from bronchial epithelial cells both in vitro and in vivo, and can reduce eosinophilic airway inflammation in an allergic inflammation model [ 43 ]. Additionally, PTRF-IL-33-ZBP1 signaling has been found to mediate macrophage necroptosis and is involved in HDM-induced airway inflammation [ 44 ]. To date, an increasing number of studies have confirmed the important role of necroptosis in asthma.…”

Cell type‐specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases

“…RIPK3 is involved in activating the NLRP3 inflammasome in infiltrating macrophages in LPS‐induced ALI, and the interaction between RIPK3 and the NLRP3 inflammasome can be hindered by RIPK3 inhibitor GSK‐872 117 . Polymerase 1 and transcript release factor (PTRF) promotes IL‐33 release, with involvement in the development of asthma 118 . ZBP1‐sensing Z‐RNA evokes necroptosis, contributing to inflammatory diseases 119 .…”

“…House dust mite (HDM) remains the dominating source of allergen in house dust, which is notably connected to asthma. PTRF mediates ZBP1‐mediated necroptosis of macrophages and airway inflammation, which can be enhanced by bronchial epithelial cell‐released IL‐33 118 (Figure 5). Aside from pyroptosis, 120 RSV infection elicits RIPK1‐, RIPK3‐, and MLKL‐based necroptosis in alveolar macrophages 121 .…”