Targeting MAC-1-dependent endothelial–immune interactions alleviates neuroinflammation after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) rapidly triggers perihematomal neuroinflammation and secondary brain injury, yet the intercellular mechanisms governing immune cell recruitment and actionable therapeutic targets remain incompletely understood. We performed single-cell RNA sequencing and cell–cell communication analyses on human perihematomal brain tissues, complemented by immunofluorescence for spatial validation. Based on these findings, we evaluated the therapeutic effects of pharmacological MAC-1 activation using LA-1 in mouse models of ICH and LPS-induced neuroinflammation. In parallel, macrophage functional assays, transcriptomic profiling, and mechanistic studies were performed to investigate the cellular and molecular mechanisms underlying MAC-1 activation. Human single-cell analyses revealed profound remodeling of endothelial-immune communication in the ICH microenvironment, characterized by enhanced ICAM1-ITGAM/ITGB2 (MAC-1)-dependent signaling. Spatial analyses confirmed close association between CD11b + myeloid cells and ICAM1-enriched vascular structures. In vivo, pharmacological activation of MAC-1 reduced neuroinflammation and immune cell infiltration, promoted hematoma resolution, and improved neurological outcomes after ICH, findings that were further validated in an LPS-induced neuroinflammation model. In vitro, MAC-1 activation enhanced macrophage-endothelial adhesion while suppressing macrophage migration and inflammatory activation, accompanied by broad inhibition of inflammatory and chemotactic transcriptional programs. Mechanistically, Dusp1 was identified as a potential downstream mediator linking MAC-1 activation to transcriptional reprogramming and reduced immune cell recruitment. MAC-1-dependent endothelial-immune interactions represent an important regulatory mechanism underlying neuroinflammation after ICH. Therapeutic activation of MAC-1 attenuates inflammatory amplification and immune cell recruitment, establishing MAC-1 as a therapeutically actionable target for limiting secondary brain injury after ICH.