J Leukoc Biol. 2025 Sep 12:qiaf129. doi: 10.1093/jleuko/qiaf129. Online ahead of print.
ABSTRACT
Autoinflammatory diseases such as CAPS (Cryopyrin-Associated Periodic Fever Syndrome) and FMF (Familial Mediterranean Fever) involve an aberrant secretion of interleukin-1β (IL-1β) due to genetic defects in the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) or pyrin inflammasomes. The regulatory mechanisms and possible interactions between inflammasome pathways remain unclear. In addition, these conditions show a high expression of the inflammatory alarmins S100A8/A9. SYK (spleen tyrosine kinase) is a known regulator of NLRP3 activity, but its connection to S100 proteins and pyrin driven inflammation has not been described so far. This study demonstrates that S100A9 controls inflammasome activation via SYK expression in monocytes Loss of S100A9 leads to decreased USP10 deubiquitinase expression, resulting in increased autophagosomal degradation of SYK. This impaires the S100A9-USP10-SYK pathway inhibiting NLRP3 inflammasome activation and reducing secretion of proinflammatory cytokines and S100A9. Strikingly, blocking this pathway in FMF monocytes unraveled a so far unknown link between pyrin and NLRP3 driven autoinflammation. These findings identify intracellular S100A9 as a direct regulator of NLRP3 activity and a driver of autoinflammatory responses.
PMID:40966542 | DOI:10.1093/jleuko/qiaf129