Adding pieces to the puzzle: IL-33 contribution to fibrogenesis in chronic lung allograft dysfunction

Interleukin-33 (IL-33) is a pleiotropic, chromatin-binding cytokine primarily expressed by non-hematopoietic cells, including endothelial cells, fibroblasts and bronchial epithelial cells. It participates in various respiratory diseases, such as acute and chronic inflammatory diseases, viral infections, lung cancer and COPD, and is known to mediate asthma and allergic conditions. IL-33 plays a dual and context-dependent role, contributing to tissue homeostasis and immune regulation under physiological conditions, while promoting inflammation and fibrosis in pathological contexts. Its signalling is mediated by the ST2 receptor, which exists in two forms: the membrane-bound ST2L that activates immune responses, and the soluble decoy receptor sST2 that negatively regulates IL-33 activity. Over the past decade, medical research has cast a spotlight on the widespread contribution of IL-33 biology not only to inflammation but also to the development of fibrosis and lung transplant rejection. A comprehensive overview of the interactions between rejection following lung transplant and IL-33 signalling is lacking. In this review, we summarize the most recent literature regarding the IL-33 in relation to chronic lung allograft dysfunction (CLAD) and acute rejection. We also discuss the potential contribution of microbial and environmental stimuli in shaping IL-33-driven type 2 and autophagic responses in the lung transplant microenvironment. Recent findings regarding therapeutic implications of IL-33 were also reported.