L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis

Macrophage adhesion and stretching have been shown to induce interleukin (IL)-1 beta production, but the mechanism of this mechanotransduction remains unclear. Here we specify the molecular link between mechanical tension on tissue-resident macrophages and activation of the NLRP3 inflammasome, which governs IL-1 beta production. NLRP3 activation enhances antimicrobial defense, but excessive NLRP3 activity causes inflammatory tissue damage in conditions such as pulmonary fibrosis and acute respiratory distress syndrome. We find that the actin-bundling protein L-plastin (LPL) significantly enhances NLRP3 assembly. Specifically, LPL enables apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) oligomerization during NLRP3 assembly by stabilizing ASC interactions with the kinase Pyk2, a component of cell-surface adhesive structures called podosomes. Upon treatment with exogenous NLRP3 activators, lung-resident alveolar macrophages (AMs) lacking LPL exhibit reduced caspase-1 activity, IL-1 beta cleavage, and gasdermin-D processing. LPL-/- mice display resistance to bleo- mycin-induced lung injury and fibrosis. These findings identify the LPL-Pyk2-ASC pathway as a target for modulation in NLRP3-mediated inflammatory conditions.

Automated summary

The actin-bundling protein L-plastin (LPL) plays a crucial role in the activation of the NLRP3 inflammasome, which is involved in IL-1 beta production. LPL stabilizes the interactions between ASC and the kinase Pyk2, enabling ASC oligomerization during NLRP3 assembly.