Centrosomal hub integrates microtubule transport, NEK7, and priming to regulate NLRP3 inflammasome activation

The NLRP3 inflammasome is a crucial component of innate immunity, playing a central role in both host defense and sterile inflammation. Dysregulated NLRP3 activation is implicated in a wide array of chronic inflammatory diseases, including autoimmune disorders, neurodegeneration, and metabolic syndromes. While its assembly at the microtubule-organizing center (centrosome) is known, the precise mechanisms governing this spatial regulation have remained elusive. Understanding how factors like NEK7, a key upstream kinase, and cellular transport converge at this hub is critical for developing targeted anti-inflammatory strategies.

Researchers investigated the spatial regulation of NLRP3 inflammasome activation in human and mouse macrophages. They systematically manipulated microtubule-dependent transport, NEK7 localization, and priming conditions. The study examined how these factors influenced NLRP3 condensation at the pericentriolar material (PCM) and subsequent inflammasome assembly. They also explored the impact of NLRP3 overexpression on activation thresholds in response to K+ efflux-dependent stimuli and the K+ efflux-independent stimulus imiquimod, assessing the roles of NEK7 and priming under these varied conditions.

The study revealed that microtubule-dependent transport is required for NEK7-dependent NLRP3 inflammasome activation, actively promoting NEK7 localization to the pericentriolar material (PCM). A critical finding was the synergistic convergence of microtubules, priming, and NEK7 on PCM abundance, thereby creating a permissive centrosomal environment for NLRP3 condensation and assembly. This integrated mechanism establishes the activation threshold and magnitude of NLRP3 inflammasome signaling. Importantly, elevated NLRP3 expression was found to compensate for limited PCM abundance, rendering K+ efflux-induced activation independent of both NEK7 and priming in human and mouse macrophages. By contrast:

NLRP3 overexpression only partially bypassed NEK7 dependence in response to the K+ efflux-independent stimulus imiquimod, suggesting distinct activation pools. This indicates a conserved spatial mechanism integrating transport, NEK7 localization, priming, and NLRP3 abundance at the PCM across species and stimuli.