Osteocalcin-expressing neutrophils from skull bone marrow exert immunosuppressive and neuroprotective effects after TBI.

Abstract

Neutrophils from skull bone marrow (N_skull) are activated under some brain stresses, but their effects on traumatic brain injury (TBI) are lacking. Here, we find N_skull infiltrates brain tissue quickly and persistently after TBI, which is distinguished by highly and specifically expressed osteocalcin (OCN) from blood-derived neutrophils (N_blood). Reprogramming of glucose metabolism by reducing glycolysis-related enzyme glyceraldehyde 3-phosphate dehydrogenase expression is involved in the antiapoptotic and proliferative abilities of OCN-expressing N_skull. The transcription factor Fos-like 1 governs the specific gene profile of N_skull including C-C motif chemokine receptor-like 2 (CCRL2), arginase 1 (Arg1), and brain-derived neurotrophic factor (BDNF) in addition to OCN. Selective knockout of CCRL2 in N_skull demonstrates that CCRL2 mediates its recruitment, whereas high Arg1 expression is consistent with its immunosuppressive effects on N_blood, and the secretion of BDNF facilitating dendritic growth contributes to its neuroprotection. Thus, our findings provide insight into the roles of N_skull in TBI.