Myeloid-specific STAT3 deletion modulates molecular activation of hippocampal microglia without morphological remodeling.

Neuroinflammation is a key mechanism driving the onset and progression of neurological and psychiatric disorders. Although the transcription factor signal transducer and activator of transcription 3 (STAT3) is critical for immune regulation, its precise role in myeloid cells remains incompletely understood. Here, we investigated how myeloid-specific STAT3 deletion (mSTAT3KO) affects hippocampal glial responses, including microglial morphology, astrocytic lipocalin-2, serum amyloid A1/2 (SAA1/2), and oxidative stress. In mSTAT3KO mice, the microglial marker Iba-1 and the microglial activation marker galectin-3 were significantly upregulated, despite no overt morphological remodeling, indicating an early stage of molecular activation toward inflammation. Astrocytic lipocalin-2 expression was markedly elevated. Similarly, serum amyloid A1 and A2 were upregulated, whereas their receptor showed no significant changes. Furthermore, the oxidative stress marker glutathione peroxidase-4 was altered following STAT3 deletion. Collectively, these findings indicate myeloid STAT3 as a pivotal regulator of hippocampal neuroinflammatory homeostasis, whose loss promotes glial activation and oxidative imbalance without structural remodeling of microglia.