Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice.
BACKGROUND
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies. This disease causes disabling neuropsychiatric symptoms even in the absence of apparent inflammation in the central nervous system (CNS), but the mechanisms involved remain unknown. Innate immune-mediated inflammation has attracted attention as a pathogenic mechanism in neuropsychiatric diseases.


METHODS
We investigated the CNS of lupus-prone mice focusing on innate immunity. Three strains of lupus-prone mice, FcγRIIB-/-Yaa, an F1 hybrid of NZB and NZW (NZB/NZW) mice, and MRL/Faslpr (MRL/lpr) mice were used to analyze CNS immunopathology.


RESULTS
Flow cytometry analysis demonstrated the numbers of brain CD45+ cells were increased compared with controls in lupus-prone mice. Upregulation of MHC class I and PDCA1 was observed in microglia and CD11b+ myeloid cells of lupus-prone mice, indicating they were activated in response to interferons (IFN). Microglial gene expression analysis of FcγRIIB-/-Yaa mice revealed the upregulation of IFN-responsive genes and inflammation-related genes including Axl, Clec7a, and Itgax, which were previously reported in neurodegenerative conditions and primed conditions. Upregulated chemokine gene expressions including Ccl5 and Cxcl10 were concurrent with increased numbers of T cells and monocytes, especially Ly6Clo monocytes in the CNS. Upregulation of Axl, Clec7a, Itgax, Ccl5, and Cxcl10 was also observed in NZB/NZW mice, indicating common lupus pathology. The primed status of microglia in FcγRIIB-/-Yaa mice was also demonstrated by morphological changes such as enlarged cell bodies with hypertrophic processes, and hyperreactivity to lipopolysaccharide. Immunohistochemistry of FcγRIIB-/-Yaa mice indicated reactive responses of astrocytes and vascular endothelium. Behavioral studies of FcγRIIB-/-Yaa mice revealed depressive-like behavior and heat hyperalgesia in the forced swim test and the tail-flick test, respectively.


CONCLUSIONS
Our data indicated that microglia in lupus exhibit a unique primed phenotype characterized by the upregulated expressions of neurodegeneration-related genes and IFN-responsive genes. Interaction with peripheral cells and brain resident cells was presumed to orchestrate neuroinflammation. Targeting innate immune cells, such as microglia and monocytes, may be a promising therapeutic approach for neuropsychiatric SLE.
['Nomura|Atsushi|A|', 'Noto|Daisuke|D|', 'Murayama|Goh|G|', 'Chiba|Asako|A|', 'Miyake|Sachiko|S|']
D000818:Animals D015551:Autoimmunity D018845:CD11 Antigens D002490:Central Nervous System D015870:Gene Expression D037181:Lectins, C-Type D008180:Lupus Erythematosus, Systemic D008810:Mice, Inbred C57BL D019463:Mice, Inbred MRL lpr D008814:Mice, Inbred NZB D008815:Mice, Inbred Strains D018345:Mice, Knockout D017628:Microglia D009000:Monocytes D022423:Myeloid Cells D017452:Receptors, IgG D013601:T-Lymphocytes
Autoimmunity Myeloid cells Monocytes Neurodegeneration Primed microglia