Glial heme oxygenase-1 regulates neuroinflammation and cerebrovascular function after mild traumatic brain injury.

The enzyme heme oxygenase-1 (HO-1) exerts neuroprotective functions through its antioxidative and anti-inflammatory properties; however, the cellular and molecular mechanisms by which HO-1 and its product carbon monoxide (CO) influence neuronal damage after traumatic brain injury (TBI) remain largely unclear. Using a murine model of single-hit mild TBI, we examined the role of glial HO-1 by comparing wild-type mice (Hmox1fl/fl) with microglia- or astrocyte-specific HO-1 knockout mice (LyzM-Cre-Hmox1fl/fl and GFAP-Cre-Hmox1fl/fl, respectively). Following injury, mice were exposed daily to either ambient air or CO. Seven days post-injury, wild-type mice exhibited significant activation of microglia and astrocytes, whereas both knockout models showed impaired glial activation, accompanied by increased cerebral vascular tone. CO administration equalized glial activation and vascular tone across wild-type and HO-1 knockout mice. Direct genotypic comparison revealed a more pronounced pro-inflammatory phenotype in GFAP-Cre-Hmox1fl/fl mice, characterized by elevated vascular tone and increased expression of inflammatory markers GFAP and NF-κB, indicating cell type-specific functions of HO-1. Collectively, our findings demonstrate that microglial and astrocytic HO-1 mediate cerebral inflammation and regulate vasospasm following TBI. Importantly, this study identifies a previously unrecognized role of astrocytic HO-1 in TBI and highlights the importance of HO-1-dependent glial interactions. The ability of CO to partially rescue the effects of HO-1 loss, further underscores the therapeutic potential of targeting the HO-1/CO pathway in TBI.