Loss of APIP in the myeloid lineage attenuates canonical NLRP3 and non-canonical caspase-11 inflammasome activation and reduces systemic inflammation in mice, whereas APIP overexpression exacerbates these responses.
APIP is a critical regulator of canonical and non-canonical inflammasomes via TRAF6 binding, presenting a potential therapeutic target for inflammatory diseases.
Apaf-1-interacting protein (APIP) has been implicated in inflammation-related processes, including myocardial infarction and cancer progression. However, its role in systemic inflammation remains elusive. Here, we investigate the APIP-mediated regulation of inflammasome activity in mice and human macrophages. Loss of APIP in the myeloid lineage (Apip cKO mice) compromises the activation of canonical NLRP3 and non-canonical caspase-11 inflammasomes, reducing pyroptosis in bone marrow-derived macrophages (BMDM). Conversely, these inflammatory responses are enhanced in BMDMs from APIP-transgenic mice. Consistently, APIP knockdown in human macrophages inhibits the activation of NLRP3 and caspase-4 inflammasomes. Mechanistically, APIP binds to TRAF6, activating downstream NF-κB and JNK signaling and facilitating the priming of both inflammasomes. Importantly, systemic inflammation induced by LPS or bacterial infection is attenuated in Apip cKO mice but exacerbated in APIP-transgenic mice. Thus, our findings suggest that APIP is crucial in regulating both canonical and non-canonical inflammasomes, presenting a potential therapeutic target for inflammatory diseases. APIP is emerging as a key regulator of inflammatory responses. Here, the authors investigate the function of APIP in regulating inflammasome activation and systemic inflammation, and identify APIP as a critical modulator of inflammasomes, with its loss impairing and its overexpression promoting canonical and non-canonical priming in vitro and in vivo by binding to TRAF6, thereby influencing systemic inflammation in mice.
Jung et al. (Wed,) conducted a other in Systemic inflammation and sepsis. APIP modulation (knockout or overexpression) vs. Wild-type or control mice/cells was evaluated on Inflammasome activation and systemic inflammation (survival, body temperature, cytokine levels). Loss of APIP in the myeloid lineage attenuates canonical NLRP3 and non-canonical caspase-11 inflammasome activation and reduces systemic inflammation in mice, whereas APIP overexpression exacerbates these responses.