MERTK-dependent efferocytosis in Cx3cr1-expressing myeloid cells supports recovery after traumatic brain injury in male mice.

Abstract

Persistent apoptotic cell burden and unresolved inflammation contribute to secondary injury after traumatic brain injury (TBI). Efferocytosis, the phagocytic removal of apoptotic cells, is a key mechanism for resolving inflammation and supporting tissue repair; however, the pathways that regulate this process after TBI remain poorly defined. We investigated the cell-specific role of efferocytosis receptor MERTK in adult male mice subjected to controlled cortical impact (CCI) injury. Conditional Mertk deletion was induced in either endothelial cells using a VE-cadherin Cre driver or Cx3cr1-expressing cells using a Cx3cr1 Cre driver. Lesion volume, blood-brain barrier (BBB) permeability, apoptotic cell accumulation, efferocytosis, cerebral blood flow (CBF), and behavioral recovery were assessed. MERTK and GAS6 were increased in the injured cortex after CCI injury and were detected in endothelial cells and Cx3cr1-expressing cells. Endothelial-specific deletion of Mertk reduced endothelial MERTK expression but did not significantly alter CCI-induced tissue damage, BBB disruption, apoptotic cell accumulation, or myeloid MERTK upregulation. In contrast, deletion of Mertk in Cx3cr1-expressing cells increased lesion volume and BBB permeability after injury compared to wild-type controls. Mertk deletion in Cx3cr1-expressing cells also led to greater accumulation of activated caspase-3+ and TUNEL+ apoptotic cells, with reduced engulfment by Cx3cr1+ phagocytes, indicating impaired efferocytosis. Mertk-deficient mice further showed reduced cerebral blood flow at 3 and 7 days after injury and impaired motor and cognitive recovery. These findings identify MERTK in Cx3cr1-expressing cells as a regulator of efferocytosis and support a protective role in limiting tissue damage, preserving vascular integrity, and promoting functional recovery after TBI in male mice.