Central role of IL-10 in CNS-protection from Inflammatory Damage during Cryptococcus Meningoencephalitis 2253926

Abstract

Abstract Introduction Cryptococcus neoformans meningoencephalitis (CM) is a highly lethal fungal disease. Th1/IFN-g are crucial for fungal clearance but are also profoundly damaging in the brain. In CM patients with inflammatory syndromes (c-IRIS/c-PIIRS), elevated T-cell responses and elevated IFN-g in cerebrospinal fluid were markers of poor prognosis and brain damage. The cytokine IL-10 is one of the major anti-inflammatory factors produced by immune cells, but its role in CM and PIIRS is unknown. Methods Using an established murine model of CM/PIIRS, we applied fungal burden analysis, flow cytometry, immunofluorescence microscopy, and single-cell RNA sequencing to assess the effects of IL10 deficiency on inflammation and pathology during CM. Additionally, a murine coma and behavioral scale (MCBS) was used to assess neurological health. IL-10-/- mice were compared to wild-type C57BL/6 counterparts. Results Our investigation revealed that: 1) IL-10 is induced in the CM brain; 2) regulatory T cells are the major source of this cytokine in the brain. Compared to WT mice, IL-10-/- mice with CM exhibited: 1) drastically worsened weight loss and neurological status of the infected mice, inducing 100% mortality despite enhanced fungal clearance; 2) increased CD45+ leukocyte infiltration into the brain, with a notable expansion of T-cells; 3) enhanced activation and inflammatory cytokine (IFN-γ and TNF-α) production by CD4+ T cells in the CNS; and 4) accelerated recruitment of monocytes and increased iNOS upregulation in these cells as well as in the resident microglia. Pathological examination further revealed increased neuronal damage in IL-10-/- mice with CM with severe depletion of the synaptic protein Syt7 at the perimeter of cryptococcal lesions and intense staining of cleaved caspase-3 in neurons, a marker of neuronal apoptosis. Conclusion These results collectively indicate that IL-10 plays a critical role during CM as an essential immunoregulatory factor protecting the brain from inflammatory damage. Funding Source U.S. Department of Veterans Affairs to MAO (1I01BX000656) U.S.Department of Veterans Affairs to MAO (1IK6BX003615) Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)