Background <p>Microgliosis and severe coagulation, including fibrinogen deposition, are features of both experimental and human cerebral malaria (CM), a lethal disease. Vascular-associated microglia migrate to coagulated cerebral vessels containing inflammatory monocytes and T cells in experimental CM. We previously showed that microglial depletion exacerbates coagulation and disease severity, including hypothermia, while anticoagulant treatment reduces microgliosis and prevents mortality. These data suggest an overall protective effect of microglia on eCM, and indicate a link between microgliosis, hypothermia, and coagulation. Therefore, mechanisms of migration and activation of microglia, T cells, and monocytes were studied in relation to the role of fibrin(ogen) in eCM.</p> Methods <p>Using both <i>Plasmodium berghei</i> ANKA infection or experimental CM, and <i>P. chabaudi</i> infection of IL-10-deficient mice (IL-10 KO), which causes a hyperinflammatory response including neuropathology, intravital two-photon microscopy and flow cytometry, were used to test patterns and mechanisms of migration. In vivo methods included intranasal administration of CCL5 receptor antagonist Met-CCL5; systemic integrin-blocking antibodies and mutant animals (IL-10 KO, ICAM1 KO), and anticoagulant treatment. Clotting-deficient mice (<i>Fga</i> KO, <i>Fib</i>^AEK) were tested for the absence of fibrinogen in clotting, while fibrinogen γ-chain mutation (Fibγ^{390–396&#xa0;A}) mice and intranasal administration of a fibrinogen γ-derived inhibitory peptide (Fibrin γ^377–395), which disrupts CD11b-fibrin interactions, assessed the role of CD11b-fibrin interactions in microglial activation in eCM.</p> Results <p>Intraluminal adhesion and crawling of CCR2^RFP+ cells, including T cells and inflammatory monocytes, was observed in cerebral vessels; however, there was no evidence that brain adherence of T cells or monocytes depends on classical adhesion molecules or coagulation. Intranasal administration of met-CCL5 reduced both microglial recruitment to vessels and CD8 T cell adherence and fibrin(ogen) deposition. Despite the previously published protective effects of the anticoagulant drug in IL-10 KO, clotting-deficient mice showed no change in <i>P. berghei</i> ANKA mortality. However, disruption of fibrin-CD11b interactions by both genetic and peptide inhibition led to exacerbated hypothermia in both experimental CM models. Reduced microglial hypertrophy also occurred in Fibrin γ^377–395 peptide-treated IL-10 KO mice infected with <i>P. chabaudi</i>.</p> Conclusions <p>These data support our previous study suggesting that microglia are involved in the regulation of hypothermia in eCM and reveal CCL5 and fibrin-CD11b signaling in microglia as key molecular pathways modulating neuroinflammation in malaria.</p>