PTPN2 sustains non-canonical inflammasome activation and shapes the inflammatory response to sepsis

Abstract

Abstract The innate immune system relies on pattern recognition receptors to recognize and detect pathogens. Gram-negative bacteria release LPS-rich outer membrane vesicles (LPS-OMVs), which activate PRRs, trigger inflammation at distant sites and contribute to systemic inflammatory conditions like sepsis. Inflammasomes, central to this response, are activated through canonical or non-canonical pathways, with intracellular LPS-OMVs stimulating the non-canonical pathway. While post-translational modifications regulate canonical signaling, those governing non-canonical activation remain poorly defined. Here, we identify Protein Tyrosine Phosphatase Non-Receptor 2 (PTPN2/TC-PTP) as a key regulator of non-canonical inflammasome activation. Using a myeloid-specific knockout mouse model of Ptpn2 , we demonstrate that Il-1b transcription is impaired due to dysregulated TLR4–p38 MAPK signaling. However, despite compromised priming, caspase-11, caspase-1 and Gasdermin-D levels remained unchanged. Our results also reveal a novel substrate for PTPN2, the Src-family kinase Lyn, which was shown to be hyperphosphorylated in the absence of Ptpn2 . Simultaneously, STAT1-mediated nitric oxide production disrupts inflammasome activity by compromising mitochondrial fitness. Lastly, Ptpn2 -deficient mice exhibit reduced small peritoneal macrophages and serum IL-1β levels in response to acute sepsis in vivo, indicating a dampened pro-inflammatory response in the absence of Ptpn2 . These findings reveal a novel role for PTPN2 in non-canonical inflammasome regulation and highlight its potential as a therapeutic target in managing systemic inflammation and sepsis.