Inhibitor of NF-κB Kinase Subunit ε Contributes to Neuropsychiatric Manifestations in Lupus-Prone Mice Through Microglial Activation.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
revised:
25
07
2022
received:
08
09
2021
accepted:
08
09
2022
pubmed:
14
9
2022
medline:
10
3
2023
entrez:
13
9
2022
Statut:
ppublish
Résumé
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiorgan dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30-40% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue-resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. This study was undertaken to explore new therapeutic targets for NPSLE focusing on microglia. RNA sequencing of microglia in MRL/lpr, lupus-prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified, and its role in microglial activation and phagocytosis was investigated using specific inhibitors and small interfering RNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL/lpr was also evaluated. Transcriptome analysis revealed the up-regulation of Ikbke, which encodes the inhibitor of NF-κB kinase subunit ɛ (IKBKε) in both microglia from MRL/lpr mice and cytokine-stimulated microglia in vitro. Intracerebroventricular administration of an IKBKε inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lpr mice. Mechanistically, IKBKε inhibition reduced glycolysis, which dampened microglial activation and phagocytosis. These findings suggest that IKBKε plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.
Substances chimiques
NF-kappa B
0
Cytokines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
411-423Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 American College of Rheumatology.
Références
Fanouriakis A, Tziolos N, Bertsias G, et al. Update οn the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis 2021;80:14-25.
Tsokos GC. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol 2020;21:605-14.
Kono M, Yasuda S, Kato M, et al. Long-term outcome in Japanese patients with lupus nephritis. Lupus 2014;23:1124-32.
Minowa K, Amano H, Ando S, et al. Disease flare patterns and predictors of systemic lupus erythematosus in a monocentric cohort of 423 Japanese patients during a long-term follow-up: The JUDE study. Mod Rheumatol 2017;27:72-6.
Bertsias GK, Boumpas DT. Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations [review]. Nat Rev Rheumatol 2010;6:358-67.
Aso K, Kono M, Kono M, et al. Low C4 as a risk factor for severe neuropsychiatric flare in patients with systemic lupus erythematosus. Lupus 2020;29:1238-47.
Kello N, Anderson E, Diamond B. Cognitive dysfunction in systemic lupus erythematosus: a case for initiating trials [review]. Arthritis Rheumatol 2019;71:1413-25.
Schwartz N, Stock AD, Putterman C. Neuropsychiatric lupus: new mechanistic insights and future treatment directions [review]. Nat Rev Rheumatol 2019;15:137-52.
Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers [review]. Nat Rev Neurol 2014;10:579-96.
Hanly JG, Kozora E, Beyea SD, et al. Nervous system disease in systemic lupus erythematosus: current status and future directions [review]. Arthritis Rheumatol 2019;71:33-42.
Borowoy AM, Pope JE, Silverman E, et al. Neuropsychiatric lupus: the prevalence and autoantibody associations depend on the definition: results from the 1000 faces of lupus cohort. Semin Arthritis Rheum 2012;42:179-85.
Hanly JG, Li Q, Su L, et al. Cerebrovascular events in systemic lupus erythematosus: results from an international inception cohort study. Arthritis Care Res (Hoboken) 2018;70:1478-87.
Omdal R, Brokstad K, Waterloo K, et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol 2005;12:392-8.
Hirohata S, Kikuchi H. Role of serum IL-6 in neuropsychiatric systemic lupus erythematosus. ACR Open Rheumatol 2021;3:42-9.
Fragoso-Loyo H, Richaud-Patin Y, Orozco-Narváez A, et al. Interleukin-6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus. Arthritis Rheum 2007;56:1242-50.
Wang JB, Li H, Wang LL, et al. Role of IL-1β, IL-6, IL-8 and IFN-γ in pathogenesis of central nervous system neuropsychiatric systemic lupus erythematous. Int J Clin Exp Med 2015;8:16658-63.
Nestor J, Arinuma Y, Huerta TS, et al. Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J Exp Med 2018;215:2554-66.
Friedman BA, Srinivasan K, Ayalon G, et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer's disease not evident in mouse models. Cell Rep 2018;22:832-47.
Chalmers SA, Wen J, Shum J, et al. CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. Clin Immunol 2017;185:100-8.
Nomura A, Noto D, Murayama G, et al. Unique primed status of microglia under the systemic autoimmune condition of lupus-prone mice. Arthritis Res Ther 2019;21:303.
Makinde HM, Winter DR, Procissi D, et al. A novel microglia-specific transcriptional signature correlates with behavioral deficits in neuropsychiatric lupus. Front Immunol 2020;11:230.
Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp 2017;126:55718.
Mike EV, Makinde HM, Der E, et al. Neuropsychiatric systemic lupus erythematosus is dependent on sphingosine-1-phosphate signaling. Front Immunol 2018;9:2189.
Stock AD, Wen J, Doerner J, et al. Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice. J Neuroinflammation 2015;12:205.
Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992;356:314-7.
Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: the MRL-lpr mouse strain as a model [review]. Autoimmun Rev 2014;13:963-73.
Crupi R, Cambiaghi M, Spatz L, et al. Reduced adult neurogenesis and altered emotional behaviors in autoimmune-prone B-cell activating factor transgenic mice. Biol Psychiatry 2010;67:558-66.
Mondal TK, Saha SK, Miller VM, et al. Autoantibody-mediated neuroinflammation: pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model. Brain Behav Immun 2008;22:949-59.
Wen J, Doerner J, Weidenheim K, et al. TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice. J Autoimmun 2015;60:40-50.
Yoshio T, Okamoto H, Kurasawa K, et al. IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus. Lupus 2016;25:997-1003.
Morris DL, Sheng Y, Zhang Y, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet 2016;48:940-6.
Zubair H, Azim S, Srivastava SK, et al. Glucose metabolism reprogrammed by overexpression of IKKε promotes pancreatic tumor growth. Cancer Res 2016;76:7254-64.
Kono M, Yoshida N, Tsokos GC. Amino acid metabolism in lupus. Front Immunol 2021;12:623844.
Vukelic M, Kono M, Tsokos GC. T cell metabolism in lupus. Immunometabolism 2020;2:e200009.
Kono M, Yoshida N, Maeda K, et al. Glutaminase 1 inhibition reduces glycolysis and ameliorates lupus-like disease in MRL/lpr mice and experimental autoimmune encephalomyelitis. Arthritis Rheumatol 2019;71:1869-78.
Kono M, Maeda K, Stocton-Gavanescu I, et al. Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation. JCI Insight 2019;4:e127395.
Prinz M, Jung S, Priller J. Microglia biology: one century of evolving concepts. Cell 2019;179:292-311.
Haruwaka K, Ikegami A, Tachibana Y, et al. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun 2019;10:5816.
Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med 2017;23:1018-27.
Huang Y, Smith DE, Ibáñez-Sandoval O, et al. Neuron-specific effects of interleukin-1β are mediated by a novel isoform of the IL-1 receptor accessory protein. J Neurosci 2011;31:18048-59.
Picon C, Jayaraman A, James R, et al. Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter. Acta Neuropathol 2021;141:585-604.
Fitzgerald KA, McWhirter SM, Faia KL, et al. IKKɛ and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003;4:491-6.
Sharma S, tenOever BR, Grandvaux N, et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 2003;300:1148-51.
Bentham J, Morris DL, Graham DS, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet 2015;47:1457-64.
Tanaka T, Murakami K, Bando Y, et al. Interferon regulatory factor 7 participates in the M1-like microglial polarization switch. Glia 2015;63:595-610.
O'Neill LA. Glycolytic reprogramming by TLRs in dendritic cells. Nat Immunol 2014;15:314-5.
Krawczyk CM, Holowka T, Sun J, et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 2010;115:4742-9.
Kelly B, O'Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 2015;25:771-84.
York EM, Zhang J, Choi HB, et al. Neuroinflammatory inhibition of synaptic long-term potentiation requires immunometabolic reprogramming of microglia. Glia 2021;69:567-78.
Jain S, Stock A, Macian F, et al. A distinct T follicular helper cell subset infiltrates the brain in murine neuropsychiatric lupus. Front Immunol 2018;9:487.