POS0461 DISRUPTED HIPPOCAMPAL NEUROGENESIS MEDIATED BY IL-6 AND IL-18 INDUCE NEUROPSYCHIATRIC CHANGES IN MURINE LUPUS

Background Systemic lupus erythematosus (SLE) frequently affects the nervous system (NPSLE), however, its pathogenesis is only partly understood. We have previously characterized behavioral phenotype of NZΒ/W-F1 lupus-prone mouse which recapitulates NPSLE exhibiting hippocampal-linked behavior including depressive-like disorder, anxiety and cognitive impairment both at early late stages disease by a profound hippocampal inflammatory response1,2. Defective neural stem cell (hNSC) response associated with dysfunction, depression anxiety, all represent common neuropsychiatric features human murine SLE. Objectives To further investigate neurogenesis in mice determine involvement pathogenesis. Methods All experiments were performed female NZW/NZB F1 C57BL/6 (WT) age 3 months (pre-nephritic) 6 (nephritic stage) (n=5-8/condition/experiment). Neurogenesis was assessed sagittal sections hippocampus immunohistochemical staining (DCX, Sox2, GFAP, Iba1) morphological criteria. RNA-sequencing tissue followed pathway enrichment analysis. Apoptosis (cleaved-caspase 3) immune infiltration (CD11b, CD45, Ly6G, Ly6C, MHC-II, CD4, CD8, B220, Iba1, CD80, CD86, Argianse-1, iNOS) flow-cytometry. Cytokines levels measured Legendplex. Ex vivo assays adult cells extracted 2-month-old WT mice. Results identified disruption (~2-fold) (decreased DCX+ cells) ad month-old together decreased differentiated time-points, suggesting that exhibit impaired neuronal differentiation. Although number precursors radial glial-like (RGLs) normal pre-nephritic stage, express increased activated RGLs (Sox2+/GFAP+) proliferating progenitors (Sox2+ indicating enhanced self-renewal ability augmented proliferation. Levels cleaved-caspase elevated supporting apoptosis. Transcriptomic analysis revealed Flow-cytometry analyses showed pronounced trafficking myeloid predominant –involving predominantly microglia- disease. Multiplex IL-6 IL-18 hippocampus. exposure hNSCs to or promoted proliferation induced Conclusion The NZB/W-F1 model SLE exhibits defective due apoptosis, differentiation progenitors. Inflammation results cytokines negatively affecting response. may induce changes mediated altered therapeutic targets NPSLE. References [1]Nikolopoulos, D., et al. “THU0223 THE NEUROPSYCHIATRIC PHENOTYPE OF NZB/W LUPUS-PRONE MOUSE MODEL AT PRE-NEPHRITIC AND NEPHRITIC STAGES DISEASE: MURINE RECAPITULATES HUMAN DISEASE.” (2020): 334-335. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1807 [2]Nikolopoulos D. “OP0040 HIPPOCAMPAL IMMUNE CELL TRAFFICKING A MYELOID PREDOMINANT INFLAMMATORY RESPONSE WITH ENHANCED ANTIGEN PRESENTATION DECREASED LEVELS NEUROTRANSMITTERS UNDERLY LUPUS MODEL.” (2021): 2021. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3972 Acknowledgements This project has received funding from European Research Council (ERC) under Union’s Horizon 2020 research innovation programme (grant agreement No 742390) Disclosure Interests None declared.