Pathogenic Effect of Chronic Stress-induced interleukin-12/23p40 on Neuropsychiatric System in Lupus-prone Mouse

Nobuya Abe¹, Kenji Oku¹, Yuichiro Fujieda¹, Nobuhiko Takahashi², Kohei Karino¹, Michihito Kono¹, Masaru Kato¹, Yuki Tanaka³, Rie Hasebe⁴, Olga Amengual¹, Miwako Yamasaki⁵, Masahiko Watanabe⁵, Masaaki Murakami³ and Tatsuya Atsumi⁶, ¹Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan, ²Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan, ³Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan, ⁴Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan, ⁵Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan, ⁶Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapparo, Hokkaido, Japan

Meeting: ACR Convergence 2020

Keywords: Mouse Models, Lupus, neuropsychiatric disorders, Neuropsychiatry, sleep, Systemic lupus erythematosus (SLE)

Session Information

Date: Saturday, November 7, 2020

Session Title: SLE – Animal Models Poster

Session Type: Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Neuropsychiatric system is one of the major organs affected in systemic lupus erythematosus (SLE). However, the pathogenesis of neuropsychiatric SLE (NPSLE) has not been fully established due to a variety of pathogenic pathways including thrombosis, autoantibodies, cytokines, and microglial activation leading to neuronal damage. Physiopsychological stress affects immune responses, putatively being a risk factor for the development of autoimmune diseases. Therefore, we have hypothesized an impact of physiopsychological stress on the pathogenesis of NPSLE, and analyzed stress-induced neuropsychiatric impairment in a murine model of lupus with the aim of establishing a novel therapeutic approach for NPSLE.

Methods: We placed chronic sleep disturbance (SD) stress for 2 weeks on 6-8-week-aged female MRL/lpr lupus prone mice and MRL/MpJ control mice using SD cage (Melquest, Japan). Open field (OF) test and elevated plus maze (EPM) test were used to assess anxiety-like behavior. We performed immunohistochemistry to evaluate neuronal and microglial activation, and Golgi-Cox staining to assess dendric morphological changes of neurons. Gene expression was comprehensively analyzed using RNA sequencing, and enzyme-linked immunoassay was used to evaluate interested protein level in cerebrospinal fluids (CSF) of the mice and of human including healthy controls and NPSLE patients.

Results: SD-subjected MRL/lpr exhibited less anxiety-like behavior than their counterparts in OF and EPM test, while control mice showed more anxiety when stressed. Stress activates ventral tegmental area, projecting medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc). In the mPFC, SD-subjected MRL/lpr demonstrated significant numbers of phospho-cFos positive activated neuronal cells whereas both SD-subjected MRL/lpr and control mice contains higher number of such than SD-free mice in NAcc. Differential gene expressions of mPFC analyzed via RNA sequencing revealed that Il12b expression level was prominent in SD-subjected MRL/lpr. Il12b is reportedly expressed in microglia. We found that SD-subjected MRL/lpr had the highest numbers of activated microglia regarding the morphology and CD68 aggregation. The CSF level of interleukin (IL)-12/23p40 encoded by Il12b was the highest in SD-subjected MRL/lpr. Furthermore, NPSLE patients also showed higher CSF IL-12/23p40 levels than healthy controls and SLE patients without neuropsychiatric symptoms. In Golgi-Cox staining, the increased numbers of dendric spines in mPFC pyramidal neurons were observed only in SD-subjected MRL/lpr.

Conclusion: Physiopsychological stress induced abnormal behavior, microglial activation and elevated level of IL-12/23p40 in lupus model mice. Moreover, IL-12/23p40 in CSF was increased in NPSLE patients, possibly associated with the development of NPSLE. Our data indicates that IL-12/23p40 is a potential therapeutic target for NPSLE.

Disclosure: N. Abe, None; K. Oku, None; Y. Fujieda, None; N. Takahashi, None; K. Karino, None; M. Kono, GlaxoSmithKline K.K., 2; M. Kato, None; Y. Tanaka, None; R. Hasebe, None; O. Amengual, None; M. Yamasaki, None; M. Watanabe, None; M. Murakami, None; T. Atsumi, AbbVie Inc., 5, 8, 9, UCB Japan Co.,Ltd., 5, 8, Eisai Co., Ltd., 8, Gilead Sciences, Inc., 5, 8, Bristol Myers Squibb Co., 2, 8, Chugai Pharmaceutical Co., Ltd., 2, 8, 9, Mitsubishi Tanabe Pharma Corporation, 8, 9, Eli Lilly Japan K.K., 2, 5, 8, Astellas Pharma Inc., 8, 9, Pfizer Inc., 2, 8, 9, Daiichi Sankyo Company, Limited, 5, 8, 9.

To cite this abstract in AMA style:

Abe N, Oku K, Fujieda Y, Takahashi N, Karino K, Kono M, Kato M, Tanaka Y, Hasebe R, Amengual O, Yamasaki M, Watanabe M, Murakami M, Atsumi T. Pathogenic Effect of Chronic Stress-induced interleukin-12/23p40 on Neuropsychiatric System in Lupus-prone Mouse [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/pathogenic-effect-of-chronic-stress-induced-interleukin-12-23p40-on-neuropsychiatric-system-in-lupus-prone-mouse/. Accessed January 15, 2021.

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