CD300f negatively regulates microglial pyroptosis via the JAK2/STAT3 axis in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a multifactorial medical condition characterized by pronounced neuroinflammation and linked to increased mortality risk and long-term cognitive impairment. Microglial pyroptosis has emerged as a crucial pathogenic mechanism in SAE. CD300f, an immune receptor expressed in microglia, regulates inflammatory processes and neuronal survival, exerting a protective effect against brain injury. However, its specific role in SAE remains unexplored. Bioinformatic analyses revealed upregulated CD300f expression in the hippocampus of SAE mice as well as in the peripheral blood of septic patients. Western blot and qPCR further confirmed increased hippocampal CD300f expression in SAE mice subjected to cecal ligation and puncture (CLP). Knockdown of CD300f promoted Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) phosphorylation, exacerbated microglial pyroptosis, aggravated neuronal damage, and worsened cognitive dysfunction in SAE mice. Conversely, CD300f overexpression attenuated lipopolysaccharide (LPS)- and adenosine triphosphate (ATP)- induced JAK2/STAT3 phosphorylation, suppressed microglial pyroptosis and proinflammatory cytokine release in vitro. Collectively, these loss- and gain-of-function data indicate that the upregulation of CD300f during sepsis represents a compensatory protective response aimed at counteracting hyperactive JAK2/STAT3 signaling and limiting pyroptotic damage. Pharmacological inhibition of STAT3 with Stattic or JAK2 with AG490 similarly inhibited STAT3 phosphorylation and attenuated microglial pyroptosis in vitro. In summary, we demonstrate that CD300f negatively regulates JAK2/STAT3 phosphorylation, attenuates microglial pyroptosis, and alleviates cognitive dysfunction in SAE mice. These findings highlight an association between CD300f and neuroprotection in SAE and suggest its potential as a therapeutic target, warranting further investigation through in vivo gain-of-function studies.