Oligodendrocytes and their role in innate immune responses depends on maturation state Saito, L.B.1, Monaco, M.C.2, Branton, W1., Cohen, É.A.3, Major, E.O.2, Power, C.1 1Universtiy of Alberta, 2National Institutes of Health (NINDS), 3Institut de Recherches Cliniques de Montréal
Multiple sclerosis (MS) is a demyelinating disease with neuroinflammation and neurodegeneration involving stress and death of oligodendrocytes (ODCs). ODCs are myelin-forming cells of the central nervous system, and remyelination competence is dictated by maturation state. Currently it is unknown if ODCs are capable in functions other than myelin formation, such as mounting an immune response. We investigated whether human ODCs could generate innate immune responses upon exposure to MS relevant inflammatory stimuli. These results were compared to immune responses observed in clinical samples. Differentiated and undifferentiated human progenitor-derived ODCs (PDOs) were exposed to TNFα for 24 hours. ODC cell markers and host immune responses were analysed by qRT-PCR. Supernatants from TNFα exposed cells were investigated by ELISA and Type I IFN bioassay. Immunofluorescence (IF) analysis on caspase-1 (CASP1) and gasdermin D (GSDMD) was performed on TNFα exposed PDOs. Total RNA was extracted from normal appearing brain white matter from MS and non-MS patients and subjected to deep sequencing. Nanostring analysis was also performed on brain sections from MS and non-MS patients. TNFα exposure induced suppression of OLIG1 and PLP. Stimulated PDOs exhibited induction of Type I IFN-associated (IFNB, IRF3, and IRF7) and inflammasome-associated (NLRP3, CASP1) genes; with greater responses observed in differentiated PDOs. MX1 and BST2 were also highly inducible in PDOs after TNFα exposure although IFNA and IFNL were not detected. CASP1 and GSDMD were detected in TNFα exposed PDOs by IF. IL-1β and IL-18 release could not be detected by stimulated PDOs, but Type I IFN activity was detected in supernatants. Analyses of human brains indicated induction of Type I IFN- and inflammasome-associated genes in MS compared to non-MS brains. Activated PDOs display innate immune responses in a differentiation state-dependent manner, with evidence of inflammasome activation. The observed immune responses also recapitulate the innate immune responses in MS brains. These processes could affect cellular survival and the potential for remyelination.