SIK3-mKO Enhances Myelin Debris Phagocytosis via CD11c Complement Pathway for White Matter Protection Poststroke

BACKGROUND: White matter preservation is a rate-limiting factor in neurological recovery after ischemic stroke and depends on efficient clearance of myelin debris by microglia/macrophages. Our prior work demonstrated that microglia/macrophage-specific SIK3 (salt-inducible kinase) knockout (SIK3-mKO) promotes an anti-inflammatory subset, enhances myelin phagocytosis, and limits white matter injury, yet the downstream molecular mechanisms remain undefined. Here, we elucidate a previously unrecognized signaling axis underlying these protective effects. METHODS: SIK3-mKO mice (SIK3 Flox+/+ ;CX3CR1 CreER ) were generated via tamoxifen-induced Cre recombination. Transient focal cerebral ischemia was induced by 60-minute transient middle cerebral artery occlusion. Neurological outcomes were assessed via Garcia, rotarod, foot-fault, and adhesive-removal tests. Immunofluorescence, flow cytometry, single-cell RNA sequencing, real-time quantitative polymerase chain reaction, ex vivo myelin phagocytosis assay, magnetic resonance imaging, and compound action potential recordings were used to characterize microglia/macrophage polarization, myelin phagocytic capacity, white matter integrity, and nerve conduction function. RESULTS: In the acute phase poststroke, SIK3-mKO selectively upregulated CD11c and its upstream complement initiator component 1q in anti-inflammatory microglia/macrophage subsets. Within the 400 to 800 µm peri-infarct zone, SIK3-mKO elevated the proportion of CD11c + microglia/macrophage by 15.1% and C1q + microglia/macrophage by 15.8% relative to wild-type controls. This CD11c-component 1q axis enhanced myelin debris clearance by 19.0% while constraining pathological engulfment of intact myelin, representing a balanced functional switch that mitigates severe demyelination. Conversely, myeloid-CD11c silencing using AAV- Itgax shRNA partially reversed SIK3-mKO-conferred protection. CD11c knockdown reduced anti-inflammatory microglia/macrophage proportions by 9.7%, attenuated physiological phagocytosis and lowered debris clearance efficiency by 7.5%, reduced MBP (myelin basic protein)-positive myelin preservation by 10.0%, and ultimately impaired white matter preservation and neurological recovery. CONCLUSIONS: We identify the SIK3-CD11c-component 1q axis as a novel pathway that orchestrates microglia/macrophage phagocytic homeostasis and preserves white matter integrity after ischemic stroke. These findings clarify SIK3 signaling in microglia/macrophage and highlight the CD11c-centered complement cascade as a promising therapeutic target for restoring white matter integrity in poststroke neurorepair.