The role of the NLRP3 inflammasome in chronic inflammation in asthma and chronic obstructive pulmonary disease

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are lung diseases characterized by airflow limitation and chronic inflammation. More and more studies have shown that the occurrence and development of asthma and COPD are related to abnormal immune responses caused by dysregulation of many genetic and environmental factors. The exact pathogenesis of the disease is still unclear. A large number of studies have shown that the NLRP3 inflammasome is involved in the process of chronic airway inflammation in asthma and COPD. Here, we summarize recent advances in the mechanism of NLRP3 inflammasome activation and regulation and its role in the pathogenesis of inflammatory lung diseases such as asthma and COPD. Meanwhile we propose possible therapeutic targets in asthma and COPD.

Keywords: COPD; NLRP3; asthma; chronic inflammation; inflammasome.

Figure 1

The composition, activation, and regulation of the NLRP3 inflammasome. The signal 1 (priming signal; left) is provided by the activation of cytokines (IL‐1β; tumor necrosis factor [TNF]‐α) or pathogen‐associated molecular patterns (PAMPs), leading to the transcriptional upregulation of NLRP3 inflammasome components (NLRP3 receptor protein; ASC; pro‐caspase‐1) and pro‐IL‐1β and pro‐IL‐18. Signal 2 (activation signal; right) is provided by any of numerous damage‐associated molecular patterns (PAMPs) or DAMPs, such as particulates, crystals and eATP. These include K⁺ efflux, Ca⁺ flux and Cl‐ efflux, the decrease of intracellular K⁺ concentration opens the Pannexin‐1, so that microbial molecules enter the cytoplasm and are recognized by LRR to activate the inflammasome. Lysosomal damage can release cathepsin E, mitochondria can products reactive oxygen species (mtROS) and mitochondrial dysfunction releases DNA, these can be recognized by LRR and activate the inflammasome. Activation of the inflammasome activates caspase 1, which cleaves pro‐IL‐1β and pro‐IL‐18 to generate active IL‐1β and IL‐18. Caspase‐1 can cut gasdermin D (GSDMD), and its N‐terminal (GSDMD‐N) can form pores in the cell membrane and induce pyroptosis. Inhibiting Toll‐like receptors (LRs) or tumor necrosis factor receptors (TNFRs) activation, IL‐10 secretion, the binding of miRNA to the NLRP3 and the expression of iNOS gene can negatively regulate the activation of NLRP3. IL, interleukin; NLRP3, LRR, leucine‐rich repeat; NOD‐like receptor pyrin domain‐related protein 3.

Figure 2

Activation/inhibition Pathway. AhR, aryl hydrocarbon receptor; CaMKII, Ca²⁺/calmodulin‐dependent protein kinase II; CSE, cigarette smoke extract; GSDMD, Gasdermin D; HSP60, heat shock protein 60; Mito Q, mitoquinone; NAC, N‐acetylcysteine; PIR, Pirin; PM, particulate matter; ROS, reactive oxygen species; SIRT1, Sirtuin1; SREBP‐1, sterol regulatory element binding protein‐1; TLR4, Toll‐like receptor 4; TREM‐1, triggering receptor expressed on myeloid cells 1; TRP, transient receptor potential protein.