Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple scleros...Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple sclerosis(MS)have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis(EAE).However,unexpectedly,progranulin-deficient mice(Grn^(−/−))were resistant to EAE,and this resistance was fully restored by wild-type bone marrow transplantation.FACS analyses revealed a loss of MHC-II-positive antigenpresenting cells in Grn^(−/−)mice and a reduction in the number of CD8+and CD4+T-cells along with a strong increase in the number of scavenger receptor class B(CD36+)phagocytes,suggesting defects in antigen presentation along with a compensatory increase in phagocytosis.Indeed,bone marrow-derived dendritic cells from Grn^(−/−)mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation.An increase in the number of CD36+phagocytes was associated with increased local inflammation at the site of immunization,stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes,an increase in the phagocytosis of E.coli particles and latex beads and defects in the clearance of the material.Hence,the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation,and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.展开更多
基金supported by the Deutsche Forschungsgemeinschaft(CRC1080,A3 to IT and MSCRC1039 to IT)the research funding program“Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz”(LOEWE)of the State of Hessen,Research Center for Translational Medicine and Pharmacology,TMP.
文摘Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple sclerosis(MS)have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis(EAE).However,unexpectedly,progranulin-deficient mice(Grn^(−/−))were resistant to EAE,and this resistance was fully restored by wild-type bone marrow transplantation.FACS analyses revealed a loss of MHC-II-positive antigenpresenting cells in Grn^(−/−)mice and a reduction in the number of CD8+and CD4+T-cells along with a strong increase in the number of scavenger receptor class B(CD36+)phagocytes,suggesting defects in antigen presentation along with a compensatory increase in phagocytosis.Indeed,bone marrow-derived dendritic cells from Grn^(−/−)mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation.An increase in the number of CD36+phagocytes was associated with increased local inflammation at the site of immunization,stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes,an increase in the phagocytosis of E.coli particles and latex beads and defects in the clearance of the material.Hence,the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation,and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.
