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

Abstract

Necroptosis is generally considered as an inflammatory cell death form. The core regulators of necroptotic signaling are receptor-interacting serine-threonine protein kinases 1 (RIPK1) and RIPK3, and the executioner, mixed lineage kinase domain-like pseudokinase (MLKL). Evidence demonstrates that necroptosis contributes profoundly to inflammatory respiratory diseases that are common public health problem. Necroptosis occurs in nearly all pulmonary cell types in the settings of inflammatory respiratory diseases. The influence of necroptosis on cells varies depending upon the type of cells, tissues, organs, etc., which is an important factor to consider. Thus, in this review, we briefly summarize the current state of knowledge regarding the biology of necroptosis, and focus on the key molecular mechanisms that define the necroptosis status of specific cell types in inflammatory respiratory diseases. We also discuss the clinical potential of small molecular inhibitors of necroptosis in treating inflammatory respiratory diseases, and describe the pathological processes that engage cross talk between necroptosis and other cell death pathways in the context of respiratory inflammation. The rapid advancement of single-cell technologies will help understand the key mechanisms underlying cell type-specific necroptosis that are critical to effectively treat pathogenic lung infections and inflammatory respiratory diseases.

Keywords: inflammation; inflammatory respiratory disease; mitochondrial dysregulation; necroptosis; oxidative stress; specific cell types.