Infiltrating CCR2+ Monocytes Drive Lethal Immunopathology during Cryptococcal Meningoencephalitis

Abstract

Abstract Cryptococcal meningoencephalitis (CM) is a major cause of CNS-related mortality worldwide. While immunosuppression can lead to cryptococcal infection, immune responses are recently also reported to promote CNS injury during CM. The role of monocytes in both anti-cryptococcal protection and the CNS pathology during CM remains unknown, but CCL2 level in CNS are linked to mortality risk in HIV-associated CM. To study the role of CCR2-axis recruited monocytes and monocyte derived cells (MDC) we evaluated outcomes of CM in WT versus CCR2-deficient mice. Fungal burdens, behavioral scores, pathology, immune parameters and mouse survival were compared. WT mice developed symptomatic disease and neurological deterioration from 3 weeks with 100% mortality by wk 5, despite a reduction in fungal burdens from wk 3 to wk 5. CCL2 production and MDC accumulation peaked at week 3, corresponding to onsets of symptoms and mouse mortality. Infiltrating MDC showed classical activation phenotypes (high level of iNOS/CD80 and low level of Arg1/CD206). In contrast, CCR2-deficient mice displayed a marked reduction in MDC recruitment relative to WT mice after infection. T cell inflammatory responses were diminished and switched from a Th1 response to mixed Th1/Th2/Th17 responses in CCR2 deficient mice. Furthermore, MDC activation shifted from M1 towards M2-type. These results show that CCR2-axis recruited MDC contributed to exuberant and detrimental Th1 inflammation. Survival of CCR2-deficient mice significantly improved despite impaired fugal clearance relative to WT mice. Taken together, we conclude that CCR2+ monocyte/MDC, while important for fungal clearance in CNS, are also critical mediators of inflammatory damage in CM.