Bone Marrow Remodeling During Experimental Cerebral Malaria Is Associated with Expansion of CXCR4hi Inflammatory Monocyte

Malaria remains a global health challenge, with cerebral malaria (CM) representing one of its most severe complications. Although inflammatory monocytes (iMON) have been implicated in CM pathogenesis, the mechanisms regulating their production and mobilization from the bone marrow (BM) during infection are not fully understood. Within the BM, CXCR4 plays a dual role by regulating monocyte retention in the hematopoietic niche and their egress into circulation. Accordingly, immature CXCR4^hi monocytes constitute a proliferative precursor pool that gives rise to the mature CXCR4^lo subset. Here, we investigated how Plasmodium berghei ANKA infection influences inflammatory monocytopoiesis in the BM of C57BL/6 mice, which are susceptible to experimental cerebral malaria (ECM), and BALB/c mice, which are resistant to this complication. BM samples were collected at days 4 and 6 post-infection and analyzed by flow cytometry. All protocols were approved by the IOC/Fiocruz Animal Ethics Committee (CEUA/IOC: L-029/2020-A2). Infection promoted the expansion of BM myeloid cells and iMON in both mouse strains, although with distinct kinetics. Notably, susceptible C57BL/6 mice exhibited a marked accumulation of CXCR4^hi iMON at day 6 post-infection, whereas BALB/c mice maintained a more balanced distribution between CXCR4^hi and CXCR4^lo subsets. BrdU incorporation and Ki67 expression further confirmed that CXCR4^hi monocytes constitute a precursor population in the BM, whereas CXCR4^lo cells remain largely non-proliferative in both steady-state and infected conditions. Collectively, our findings indicate that ECM-susceptible mice exhibited altered BM inflammatory monocytopoiesis, characterized by the preferential expansion of immature CXCR4^hi monocytes. These results highlight the BM as an active regulator of the inflammatory response during malaria and suggest that dysregulated CXCR4-dependent monocytopoiesis may contribute to CM immunopathogenesis.