NLRP1 drives inflammasome responses in the human respiratory epithelium

Abstract

The airway epithelium is now considered crucial to the orchestration of respiratory inflammatory responses and tissue remodelling. It functions as the first line of defence against inhaled concomitants and coordinates the resulting innate and adaptive immune pathways. Little information is available, however, on epithelial inflammasomes, particularly their functions and contributions to chronic respiratory diseases. Here it was observed that although most inflammasome components were present in human bronchial epithelium, minimal inflammasome responses were detected following infections with common respiratory bacteria. Optimal inflammasome priming occurs following TLR3 stimulation which suggests that these cells may instead mediate antiviral responses. In parallel with a recent publication, shown here is that NLRP1 is the dominant inflammasome in primary bronchial epithelial cells (Robinson et al., 2020). These cells fail to respond to NLRP3, NLRC4 and AIM2 inflammasome stimuli. In contrast, basal and air-liquid interface-differentiated cells activate NLRP1 to undergo cell death and cytokine secretion upon Valinyl-L-boroproline treatment. In COPD patients, IL-1? levels in the airways may be enhanced compared with healthy smokers, correlating with exacerbation frequency. Bronchial epithelial cells may contribute to the disease since the expression of NLRP1 and its negative regulators, dipeptidyl peptidase 8 and 9 (DPP8/9), are elevated in basal cells from patients with COPD. Valinyl-L-boroproline inhibition of DPP8/9 in these cells leads to marked inflammasome activation, which is dependent on caspase or proteasome activity and is reduced by knockdown or knockout of NLRP1. In addition to basal cells, NLRP1 activation is also enhanced in air-liquid interface-differentiated cells from COPD patients in response to Valinyl-L-boroproline or human rhinovirus 16. Preliminary evidence suggests that chronic Valinyl-L-boroproline treatment during differentiation leads to sustained NLRP1 inflammasome activation and arrested epithelial development. Following CRISPR/Cas9-mediated NLRP1 knockout, progenitor cell numbers (the intermediate stage between basal cells and terminally differentiated cells) are reduced, implicating NLRP1 in initial cell fate decisions. Targeting the NLRP1 inflammasome pathway may, therefore, be a novel therapeutic approach for the treatment of conditions such as COPD viral exacerbations, as well as other disorders involving dysregulated epithelial differentiation.