The Murine Antimicrobial Peptide CRAMP Alleviates Neuroinflammation By Downregulating the cGAS-STING Signalling Pathway.

Facial nerve injury (FNI) is common, yet therapeutic outcomes are often suboptimal due to axonal degeneration, neuronal death, and persistent neuroinflammation. Microglia, the primary immune cells of the central nervous system, exacerbate neuroinflammation when polarized to the pro-inflammatory M1 state. Cathelicidin-related antimicrobial peptide (CRAMP in mice and rats; LL-37 in humans) has been shown to mitigate neuroinflammation by inhibiting microglial M1 polarization via suppression of the cGAS-STING signalling pathway, suggesting a potential therapeutic strategy for FNI. This study employed both in vivo and in vitro approaches to investigate the regulatory roles of the cGAS-STING pathway and murine CRAMP in neuroinflammatory processes. In vivo, a murine FNI model was established. Quantitative analysis of facial nucleus neurons was performed using TUNEL and Nissl staining, combined with cerebral blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI). FNI was found to activate the cGAS-STING signalling pathway. Inhibition of this pathway attenuated neuroinflammation, reduced apoptosis in the facial nucleus, and improved functional recovery. CRAMP treatment yielded therapeutic effects comparable to those of the established STING inhibitor H151. Furthermore, BOLD-fMRI revealed that CRAMP partially reversed abnormal local neural activity and disrupted functional connectivity within the central nervous system following FNI, thereby promoting recovery of facial nerve function. In vitro, an LPS-induced neuroinflammation model was utilized. Lipopolysaccharide (LPS)-induced BV-2 microglial inflammation model was used to examine the regulatory effect of CRAMP on the cGAS-STING pathway and neuroinflammation. LPS stimulation promoted M1 polarization of microglia, which coincided with activation of the cGAS-STING pathway. CRAMP was found to inhibit this signaling pathway and inhibit LPS-induced M1 polarization. These findings systematically validate the cGAS-STING pathway as a potential therapeutic target for FNI and demonstrate that CRAMP exerts anti-neuroinflammatory and neuroprotective effects through modulation of this pathway. This study elucidates the critical role of CRAMP in regulating innate immune activation and proposes a novel immunotherapeutic strategy for FNI.