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Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression

Nature Immunology volume 25, pages 671–681 (2024)Cite this article

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Abstract

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.

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Fig. 1: Microglia are activated by neuronal HMGB1.
Fig. 2: DNRAbs induce microglial activation through RAGE.
Fig. 3: Treatment with ACE inhibitors requires LAIR-1 for efficacy.
Fig. 4: Hippocampal microglial scRNA-seq shows that ACE inhibitors mitigate DNRAb phenotype.
Fig. 5: ARB replicates effects of ACE inhibitors on neurons and microglia.
Fig. 6: IL-10 is induced by HMGB1 and suppresses Lair1 expression.
Fig. 7: Outcomes of DNRAb-mediated neuronal damage.

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Data availability

The accession no. for the sequencing data reported in the present study is Gene Expression Omnibus (GEO) GSE230077 and can also be accessed through a single-cell portal, accession no. SCP2193. Previously published datasets used in identifying and naming clusters are publicly available: Allen Brain Atlas, GEO accession nos. GSE121654 and GSE152184. Previously published datasets used for microglial comparisons are publicly available at: GEO, accession no. GSE98971; Mendeley Data (1, 2): GEO accession no. GSE101689.

Code availability

Customized code can be accessed at https://github.com/seanken/LupusModel.

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Acknowledgements

We thank R. A. Berlin and H. Khalili for their technical assistance. We also thank Y. Atisha-Fregoso, M. Lesser, R. Rasul, H. Rahman and C. Chuizan for their statistical expertise. The present study was supported by grants from the National Institutes of Health (NIH grant no. 1P01AI073693) to B.D. and J.Z.L.

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  1. These authors contributed equally: Kaitlin R. Carroll, Mark Mizrachi.

Authors and Affiliations

  1. Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, USA

    Kaitlin R. Carroll, Mark Mizrachi, Bahtiyar Toz, Czeslawa Kowal, Jeffrey Wingard, Nazila Tehrani, Aida Zarfeshani, Rachel Weissman-Tsukamoto, Bruce T. Volpe & Betty Diamond

  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Sean Simmons & Joshua Z. Levin

  3. Northwell Health, Manhasset, NY, USA

    Nina Kello & Lara El Khoury

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Contributions

K.R.C., M.M. and S.S. wrote and edited the paper and designed, performed and analyzed experiments. B.T. designed, performed, and analyzed experiments. J.W., A.Z., N.K. and L.E.K. performed and analyzed experiments. N.T. and R.W.T. performed experiments. C.K. designed, performed and analyzed experiments and edited the paper. J.Z.L. designed and analyzed experiments, edited the paper and oversaw the studies. B.T.V. designed, performed and analyzed experiments, edited the paper and oversaw the studies. B.D. designed and analyzed experiments, wrote and edited the paper and oversaw the studies.

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Correspondence to Betty Diamond.

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Extended data

Extended Data Fig. 1 Pathology is sustained for at least 12 months.

a) Decreased dendritic complexity in 12 month old (m.o.) Balb/c DNRAb+ compared with DNRAb− mice (mean +/− SEM; n = 4-5 mice per group; n = 55-59 neurons analyzed per group; two-tailed linear mixed model test with Tukey adjustment; p = 0.016). b) Decreased dendritic spine density in 12 m.o. Balb/c DNRAb+ compared with DNRAb− mice (median (solid line) with quartiles (dash); n = 4 mice per group; n = 15-18 neurons analyzed per group; two-tailed Mann-Whitney test; p < 0.0001). c) Representative sections of microglia in CA1 stratum radiatum stained for Iba1 (red) and CD68 (white) in 12 m.o. DNRAb+ and DNRAb− Balb/c mice (n = 3 mice per group). d) Increased activation score in 12 m.o. Balb/c DNRAb+ microglia compared to 12 m.o. Balb/c DNRAb− counterparts based on morphology and CD68 expression (median (solid line) with quartiles (dash); n = 3 mice per group; n = 110-169 microglia scored per group; two-tailed Mann-Whitney test; p < 0.0001).

Extended Data Fig. 2 Ex vivo adult microglia and neonatal cultures respond similarly to HMGB1.

Increased mRNA expression for a) Tnf (p = 0.0019); b) Il1b (p = 0.0030); c) C1qa (p = 0.1302); and d) Ifnb1 (p = 0.0453) in B6 microglia stimulated with 1 μg/ml HMGB1 compared with unstimulated microglia cultured in medium for 6 hours (mean +/− SD; ex vivo microglia isolated from 3-4 B6 mice; two-tailed unpaired t-test).

Extended Data Fig. 3 Acute neuronal loss is not affected by loss of RAGE or microglial LAIR-1.

a) Decreased CA1 neurons in WT B6 (p = 0.0004) and RAGE KO mDNRAb+ (p < 0.0001) mice compared to their mDNRAb− counterparts (median (solid line) with quartiles (dash); n = 3-4 mice per group; n = 72-96 sections per group; two-tailed Kruskal-Wallis test). b) Decreased CA1 neurons in LAIR-1 cKO DNRAb+ mice compared to DNRAb− (median (solid line) with quartiles (dash); n = 3 mice per group; n = 67-98 sections per group; two-tailed Mann-Whitney test; p = 0.0394).

Extended Data Fig. 4 Single-cell RNA-seq clustering and quality control.

a) UMAP plot colored by clustering. b) UMAP plot split by mouse of origin, colored by cell type. No evidence of strong batch effects in the UMAP space. c) Violin plot of various QC metrics of interest, with similar distributions observed in each mouse. QC metrics include the score returned by Azimuth (Azimuth Score), number of genes per cell (nGene), number of UMI per cell (nUMI), percent UMI coming from mitochondrial reads (Percent Mitochondrial), percent UMI mapping to ribosomal proteins (Percent Ribosomal Protein), and doublet scores (scds). d) Feature plots of genes associated with a known microglia activation signature73. Subclustering within microglia subtypes is largely driven by these variables. e) Feature plots of number of genes per cell (nGene) and number of UMIs per cell (nUMI). Subclustering within microglia subtypes is largely driven by these variables.

Extended Data Fig. 5 Concordance score of Ms4a7+ microglia with microglial gene signatures.

a) Higher DAM signature gene set score in Ms4a7+ compared with Homeostatic microglia (Keren-Shaul et al. (2017)35 median (solid line) with quartiles (dash); n = 3 mice per group; n = 2515-15285 cells/cluster; two-tailed Mann-Whitney test; p < 0.0001). b) Lower Homeostatic signature gene set score in Homeostatic compared with Ms4a7+ cluster (Keren-Shaul et al.35; median (solid line) with quartiles (dash); n = 3 mice per group; n = 2515-15285 cells/cluster; two-tailed Mann-Whitney test; p < 0.0001). c) Higher NPSLE signature gene set score in Ms4a7+ compared with Homeostatic microglia (Makinde et al.38; median (solid line) with quartiles (dash); n = 3 mice per group; n = 2515-15285 cells/cluster; two-tailed Mann-Whitney test; p < 0.0001). d) Higher MGnD signature gene set score in Ms4a7+ compared with Homeostatic microglia (Krasemann et al.39; median (solid line) with quartiles (dash); n = 3 mice per group; n = 2515-15285 cells/cluster; two-tailed Mann-Whitney test; p < 0.0001).

Extended Data Table 1 ScRNA-seq quality control metrics summary
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Extended Data Table 2 ScRNA-seq cell cluster composition frequency and percentage
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Extended Data Table 3 ScRNA-seq cell cluster comparison statistics
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Extended Data Table 4 ScRNA-seq gene expression in Ms4a7+ cluster by sample
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Extended Data Table 5 ScRNA-seq Ms4a7+ cell gene expression comparison statistics
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Carroll, K.R., Mizrachi, M., Simmons, S. et al. Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression. Nat Immunol 25, 671–681 (2024). https://doi.org/10.1038/s41590-024-01772-6

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