Fate mapping of peripherally derived macrophages reveals a long-lasting engrafted population that maintains a distinct transcriptomic profile for up to 8 months after Traumatic Brain Injury

Traumatic Brain Injury (TBI) is one of the most established environmental risk factors for the development of dementia and long term neurological deficits representing a critical health problem for our society. It is well-established that TBI-induced neuroinflammation contributes to the long-lasting cognitive deficits and engages brain-resident macrophages (microglia) as well as monocytes-derived macrophages (MDMs) recruited from the periphery. While numerous studies have characterized microglia response to TBI, and the critical role of early infiltrated MDMs in the development of cognitive dysfunctions, the fate of MDMs in TBI remains unknown. Microglia and MDMs have distinct embryological origins and it is unclear if MDMs can fully transition to microglia after infiltrating the brain. This gap in knowledge is due to the fact that after brain engraftment, MDMs stop expressing their signature markers, thus making discrimination from resident microglia cells elusive. Here, for the first time, we longitudinally trace the fate of MDMs by taking advantage of two complementary yet distinct fate mapping mouse lines, CCR2-creERT2 and Ms4a3-cre, where inflammatory monocytes are permanently labeled even after in situ reprogramming. We demonstrated that early infiltrated MDMs persist in the brain for up to 8 months after TBI in adult female and male mice. Notably, MDMs retain their phagocytic activity while remaining transcriptomically distinct from microglia, and show a signature associated with aging and disease. Our data significantly advance the understanding of long-lasting MDMs and provide critical knowledge for developing more targeted therapeutic interventions for myeloid cells.