Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice

Abstract

BackgroundSystemic 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.MethodsWe 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.ResultsFlow 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.ConclusionsOur 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.

Different Spatial and Temporal Roles of Monocytes and Monocyte-Derived Cells in the Pathogenesis of an Imiquimod Induced Lupus Model

“…RNA-seq analysis showed the upregulation of Cxcl13 in IMQ-induced K-Ly6C lo from IMQ-treated mice and PCR analysis revealed its expression was even higher in MHCII low MF and MF from IMQ-treated mice. The CCL5/CCR5 axis was previously reported to be involved in the recruitment of Ly6C lo monocytes to tissues ( 25 ). Ccl5 was upregulated in IMQ-induced K-Ly6C lo and lower in MF ( Figure 5D ).…”

Pyruvate kinase isoform M2 impairs cognition in systemic lupus erythematosus by promoting microglial synaptic pruning via the β-catenin signaling pathway

“…Microglia activation is a common pathological feature of a range of neurodegenerative diseases, including Alzheimer’s disease (AD) [ 27 – 29 ]. Also, microglia have a major role in NPSLE, and their abnormal activation has been detected in the hippocampus of several strains of lupus-prone mice (NZB/NZW, MRL/lpr, and FcγRIIB −/− Yaa) [ 30 ]. In the process of continuous inflammation, activated microglia-phagocytosed astrocytes promote neuronal apoptosis and aggravate depression index and cognitive dysfunction in mice with lupus [ 31 – 33 ].…”

Dexamethasone reduces autoantibody levels in MRL/lpr mice by inhibiting Tfh cell responses

“…Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abundant production of autoantibodies, particularly anti‐nuclear (ANA) and anti‐dsDNA antibodies 1‐4 . Recently, the role of T follicular helper (Tfh) in antibody production has attracted much attention.…”