Cranial bone marrow-derived monocytes fuel neuroinflammation in chronic traumatic brain injury_Mus muscles (PRJCA048493)
Chronic traumatic brain injury (cTBI) patients experience long-term progressive neurological decline, which is severe in aged patients, while the underlying mechanisms remain unclear. Cranial bone marrow has been appreciated as an adjacent immune surveillance organ of brain, which rapidly responses to acute brain injury. In cTBI patients, the cranial bone marrow exhibits persistent aberrant myelopoiesis, manifested as an expansion of inflammatory monocyte/macrophage (Mo/Mac), which are more pronounced in aged patients. These cranial bone marrow-derived Mo/Mac actively migrate into brain parenchyma, where they fuel chronic neuroinflammation and drive neurological deficits. Mechanistically, age-related PPARa deficiency causes lipid metabolism dysfunction in these Mo/Mac, enhancing H3K4me3-mediated regulation of inflammatory chromatin states and thereby promoting neuroinflammation. Activation of PPARa via fenofibrate rectifies Mo/Mac lipid metabolism, reduces inflammatory Mo/Mac infiltrating the brain. Importantly, in our proof-of-concept clinical trial enrolled 40 aged cTBI patients, fenofibrate treatment reduced plasma neurofilament light chain levels and improved cognitive functions. This study reveals the cranial bone marrow-derived Mo/Mac as a key driver of cTBI-related neuroinflammation and suggests PPARa as an ideal treatment target to improve long-term neurological outcome in cTBI.