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Fasting-activated ventrolateral medulla neurons regulate T cell homing and suppress autoimmune disease in mice

Nature Neuroscience volume 27, pages 462–470 (2024)Cite this article

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Abstract

Dietary fasting markedly influences the distribution and function of immune cells and exerts potent immunosuppressive effects. However, the mechanisms through which fasting regulates immunity remain obscure. Here we report that catecholaminergic (CA) neurons in the ventrolateral medulla (VLM) are activated during fasting in mice, and we demonstrate that the activity of these CA neurons impacts the distribution of T cells and the development of autoimmune disease in an experimental autoimmune encephalomyelitis (EAE) model. Ablation of VLM CA neurons largely reversed fasting-mediated T cell redistribution. Activation of these neurons drove T cell homing to bone marrow in a CXCR4/CXCL12 axis-dependent manner, which may be mediated by a neural circuit that stimulates corticosterone secretion. Similar to fasting, the continuous activation of VLM CA neurons suppressed T cell activation, proliferation, differentiation and cytokine production in autoimmune mouse models and substantially alleviated disease symptoms. Collectively, our study demonstrates neuronal control of inflammation and T cell distribution, suggesting a neural mechanism underlying fasting-mediated immune regulation.

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Fig. 1: Orexigenic CAVLM neurons are required and sufficient for fasting-mediated T cell redistribution.
Fig. 2: CAVLM neurons drive T cell homing to the BM in a CXCR4/CXCL12 axis-dependent manner.
Fig. 3: The CAVLM→CRHPVN neural circuit drives T cell blood-to-BM homing.
Fig. 4: CAVLM neuron-activated mice are resistant to EAE pathogenesis and neuroinflammation.
Fig. 5: Multiple factors contribute to EAE improvements in CAVLM neuron-activated mice.

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Data availability

The RNA expression datasets generated in this study are available at the Gene Expression Omnibus (accession numbers GSE170737 (token cdghyikqtxgvjuz) and GSE209639 (token exsfemawbtstfwn)). Raw values associated with each figure panel can be found in the Source Data files. Other data supporting the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

This study did not use any customized code or mathematical algorithm.

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Acknowledgements

We thank M. Luo, R. Lin, Y. Li, B. Li and K. Mao for their suggestions on the manuscript. We thank S. Zhang (X. Wang’s laboratory at the NIBS), C. Lv at the Shandong Analysis and Test Center and F. Zheng at Huazhong University of Science and Technology for teaching us to establish the EAE mouse model. We thank Y. Tao and L. Tang at the National Center for Protein Sciences for providing advice in immunological experiments. We thank the NIBS imaging facility staff—T. Cai and J. Wang (NIBS sequencing core facility), J. Chen (Chinese Institute for Brain Research flow cytometry facility) and M. Gou (C. Dong’s laboratory at Tsinghua University)—for technical assistance. We thank G. Pang for drawing the schematics. C.Z. is supported by grants from the National Natural Science Foundation of China (31822026, 32271063 and 31500860), research funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYPY20220018) and the National Science and Technology Innovation 2030 Major Project of China (2021ZD0203900). J.C. is supported by a grant from the National Natural Science Foundation of China (32100821). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Research Center for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Liang Wang, Yuchen Wang & Cheng Zhan

  2. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China

    Mingxiu Cheng & Cheng Zhan

  3. National Institute of Biological Sciences, Beijing, China

    Mingxiu Cheng & Cheng Zhan

  4. School of Sport Science, Beijing Sport University, Beijing, China

    Jing Chen

  5. School of Life Sciences, Fudan University, Shanghai, China

    Famin Xie

  6. Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, China

    Li-Hao Huang

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Contributions

C.Z. conceived the study and wrote the manuscript. L.W. and Y.W. performed viral injections, flow cytometry and immunization of mice. M.C. conducted in situ hybridization. J.C. measured food intake. F.X. analyzed the RNA sequencing data. L.-H.H. provided intellectual expertise and helped to interpret the experimental results.

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Correspondence to Cheng Zhan.

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Extended data

Extended Data Fig. 1 Dietary fasting redistributes T cells.

a, Gating strategy used for analyzing T-cell in the blood, BM, spleen, and LN. Starting from the upper left panel and going down following the arrows in dotted lines, we gated successively: LIVE cells in R1, CD45+ cells, and T cells. T cells were subdivided into CD4+ T and CD8+ T-cell subsets. 123count eBeads were added to cell suspensions for absolute cell counting. b, Absolute cell counts of T cells in the blood (T p = 0.038, CD4+ T p = 0.021, CD8+ T p = 0.038), BM (T p = 0.0063, CD4+ T p = 0.028, CD8+ T p = 0.0059), spleen (T p = 0.013, CD4+ T p = 0.021, CD8+ T p = 0.0079), and LNs (T p = 0.024, CD4+ T p = 0.027, CD8+ T p = 0.024) of WT mice fed ad libitum or fasted for 24 hours. c, d, Percentages of dead (FVD+) T cells (c, blood p = 0.35, BM p = 0.23) and Ki67+ T cells (d, blood p = 0.71, BM p = 0.27) in the blood and BM of WT mice fed ad libitum or fasted for 24 hours. Each symbol represents an individual mouse. Mean ± s.e.m. Two-sided unpaired t-test was used in b and c. *p < 0.05, **p < 0.01, ***p < 0.001, ns: not significant.

Source data

Extended Data Fig. 2 Six days of CAVLM neuronal activation changes T-cell counts in the blood and lymphoid organs.

a, The experimental workflow. Three weeks after AAV viral injections into the VLM of Dbh-Cre mice, mice received CNO injections once daily for six days. b, Absolute T-cell counts in the blood (T p = 0.0001, CD4+ T p = 0.0004, CD8+ T p < 0.0001), BM (T p = 0.0007, CD4+ T p = 0.0023, CD8+ T p = 0.0005), spleen (T p = 0.032, CD4+ T p = 0.028, CD8+ T p = 0.058), and LNs (T p = 0.022, CD4+ T p = 0.021, CD8+ T p = 0.025) of DbhVLM-hM3Dq and DbhVLM-mCherrry mice after six days of CNO injections. c, Absolute T-cell counts in the blood, BM, spleen, and LNs of WT mice 4 hours after CNO or saline injection. Each symbol represents an individual mouse. Mean ± s.e.m. Two-sided unpaired t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ns: not significant.

Source data

Extended Data Fig. 3 The impacts of chemogenetic activation of CA neurons on T-cell death, proliferation, and migration.

a, Percentages of dead (FVD+) T cells in the blood and BM of DbhVLM-hM3Dq and DbhVLM-mCherry mice 4 hours after CNO injection. b, Percentages of Ki67+ cells in T cells in the blood and BM (p = 0.0012) of DbhVLM-hM3Dq and DbhVLM-mCherry mice 12 hours after CNO injection. c, Absolute cell counts of transferred T cells in the spleen and LNs of DbhVLM-hM3Dq and DbhVLM-mCherry mice at 4, 8, 12, and 24 hours after CNO injections (mCherry: 4 hours n = 8; 8, 12 and 24 hours n = 7. hM3Dq: 4 and 12 hours n = 7; 8 and 24 hours n = 8 mice. spleen p = 0.027; LN p < 0.0001, p = 0.0011). Experimental schematic (left panel). Each symbol represents an individual mouse. Mean ± s.e.m. Two-sided unpaired t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ns: not significant.

Source data

Extended Data Fig. 4 Activation of CAVLM neurons up-regulates the CXCR4 expression by immune cells in BM.

a, Experimental flow for comparing mRNA expression by immune cells (CD45+) between DbhVLM-hM3Dq mice and DbhVLM-mCherrry. b, Volcano plot showing 422 upregulated genes (red dots) and 198 downregulated genes (blue dots) in BM CD45+ cells of DbhVLM-hM3Dq mice compared to those of DbhVLM-mCherrry mice (n = 4 mice per group). c, Heatmap showing differentially expressed genes associated with cell migration. The Cxcr4 gene is boxed in red. d, Experimental schematic of VLM activation in Cxcl12fl/fl×nestin-Cre×Dbh-flpo (cxcl12−/-) mice (left panel). AAV-flpo-hM3Dq-mCherry was injected into the VLM of Nestin-Cre×Cxcl12flox/flox×Dbh-flpo mice (Cxcl12-/-) to express hM3Dq in CAVLM neurons. A representative image showing that the majority (~ 90%, 1741 hM3Dq+ neurons from 2 mice) of hM3Dq+ neurons (red) in the VLM of cxcl12-/- mice are TH+ (right panel). e, CXCR4 expression by T cells in the BM of WT mice and Cxcl12-/- mice (p < 0.0001). Each symbol represents an individual mouse. Mean ± s.e.m. Two-sided unpaired t-test. ***p < 0.001.

Source data

Extended Data Fig. 5 Whole brain projections of CAVLM neurons.

a, A representative sagittal image showing VLM-derived axonal projections (green) throughout the brain. NTS, nucleus tractus solitarius. DR, dorsal raphe. PVT, paraventricular thalamic nucleus. DMH, dorsal medial hypothalamus. ARC, arcuate nucleus. POA, preoptic area. b-d, Selective inhibition of the CAVLM→ARC neural circuit by bilateral infusion of CNO (0.5 µl each side, 1 µg/µl dissolved in saline) into the ARC via pre-implanted cannulas. b, Experimental schematic. c, A representative image shows the position of cannulas targeting the ARC. d, Absolute cell counts of transferred T cells in blood (p = 0.022) and BM (p = 0.034) after bilateral infusion of CNO into the ARC of DbhVLM-hM4Di mice. e-g, Selective inhibition of the CAVLM→DMH neural circuit by bilateral infusion of CNO (0.5 µl each side, 1 µg/µl dissolved in saline) into the DMH via preimplanted cannulas. e, Experimental schematic. f, A representative image shows the position of cannulas targeting the DMH. g, Absolute cell counts of transferred T cells in blood (p = 0.0062) and BM (p = 0.039) after bilateral infusion of CNO into the DMH of DbhVLM-hM4Di mice. h-j, Transsynaptic anterograde tracing of VLM neurons. h, Schematic of transsynaptic anterograde tracing. AAV1-Cre was injected into the VLM of Ai14 mice. i, Representative images showing VLM transsynaptic labeled tdTomato+ neurons (red) and Crh+ neurons (green) in the PVN. Arrows indicate double-labeled neurons. j, Pie graphs showing the percentages of CRHPVN neurons that received inputs from the VLM (558 double-labeled neurons among 1717 Crh+ neurons from 2 mice). k, l, CRH neurons in the PVN of Crh-Cre×Ai14 mice were activated by 24 hours of fasting. k, Representative images show Fos expression (green) in PVN CRH neurons (red) of mice fed ad libitum (top) or fasted (bottom). l, Group data (number p = 0.0014, percentage p < 0.0001). Data are presented as Mean ± s.e.m in d, g, and l. Two-sided unpaired t-test was used in d, g, and l.

Source data

Extended Data Fig. 6 Adrenal glands are peripheral mediators of CAVLM neuronal activation-induced blood-to-BM homing of immune cells.

a, Corticosterone levels in the plasma of DbhVLM-hM3Dq and control mice 4 hours after CNO injection (p < 0.0001; mCherry n = 5, hM3Dq n = 6 biologically independent samples). b-d, Administration of dexamethasone drove far red dye-labeled (FR+) T-cell homing to the BM. b, Experimental schematic. T-cell CXCR4 expression in the BM (c, p = 0.00062) and absolute cell counts (d, blood p = 0.0015, BM p = 0.013) of transferred T-cell 4 hours after administration of saline or dexamethasone (saline n = 6, dexamethasone n = 6 biologically independent samples). Each symbol represents an individual mouse. Mean ± s.e.m. Two-sided unpaired t-test. *p < 0.05, **p < 0.01, ***p < 0.001.

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Extended Data Fig. 7 Activation of CAVLM neurons alleviates EAE autoimmune disorders.

a, Body weight changes in DbhVLM-hM3Dq and DbhVLM-mCherry mice after EAE induction. Two-way ANOVA: time F(3.307, 79.38) = 7.375, p = 0.0001; mice group F(1, 24) = 41.08, p < 0.0001; interaction between time and mice group F(23,552) = 8.232, p < 0.0001. b, Levels of cytokines in the spinal cord of CAVLM neuron-activated mice and control mice fed ad libitum or on an IF diet at day 17 after EAE induction (mCherry Ad n = 11, hM3Dq Ad n = 9; ctrl IF n = 10 biologically independent samples). c, d, Longitudinal investigations of the impact of CAVLM neuronal activation on T-cell distribution in EAE mice. c, The experimental workflow. d, Absolute T-cell counts in the blood, BM, spleen, and draining LN of DbhVLM-hM3Dq and DbhVLM-mCherrry mice on days 7, 14, and 21 after EAE induction (blood mCherry: day 7 n = 12, day 14 n = 11, day 21 n = 9; blood hM3Dq: day 7 n = 9, day 14 n = 11, day 21 n = 8; BM mCherry: day 7 n = 5, day 14 n = 5, day 21 n = 3; BM hM3Dq: day 7 n = 6, day 14 n = 5, day 21 n = 4; spleen mCherry: day 7 n = 14, day 14 n = 11, day 21 n = 9; spleen hM3Dq: day 7 n = 18, day 14 n = 12, day 21 n = 8; LN mCherry: day 7 n = 11, day 14 n = 11, day 21 n = 9; LN hM3Dq: day 7 n = 11, day 14 n = 14, day 21 n = 8 biologically independent samples). All mice received CNO injection once daily after EAE induction until study termination. Each symbol represents an individual mouse. Mean ± s.e.m. Two-sided unpaired t-test in b and d. The p values in b and d are in source data files.

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Extended Data Fig. 8 Activation of CAVLM neurons inhibits the T-cell response in SLOs during EAE.

a, Flow cytometric analysis of the activation status of CD8+ T cells in the spleen of CAVLM neuron-activated mice and control mice fed ad libitum or on an IF diet at day 17 after EAE induction. Data are presented as representative plots (top panels) and quantified absolute cell numbers and percentages (bottom panels) (mCherry n = 11, hM3Dq n = 9; ctrl n = 10 biologically independent samples. Number hM3Dq p = 0.045, ctrl p = 0.012; percentage hM3Dq p = 0.023, ctrl p = 0.042). b, Activation of CAVLM neurons had no impact on plasma IFNγ and IL17A levels in non-disease mice. c, GO-BP analysis shows the most significantly enriched biological processes in CD4+T cells sorted from the spleen of CAVLM neuron-activated mice and control mice at day 7 after EAE induction. Genes were considered to be significantly differentially expressed using a false discovery rate of 0.05 and a fold change of 1.5 in an R package (cluster Profiler version 3.14.3). d, Heatmap showing differentially expressed genes associated with the MAPK and NF-κB signaling pathways. All mice received CNO injection once daily after EAE induction until study termination. Each symbol represents an individual mouse. Mean ± s.e.m. Two-sided unpaired t-test was used in a, b.

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Extended Data Fig. 9 Continuous activation of CAVLM neurons alleviates IMQ-induced psoriasis-like skin inflammation and suppresses the mBSA-induced DTH response in mice.

a-d, IMQ-induced back skin inflammation was scored daily based on the change in skin thickness (a), erythema (b), skin scaling (c), and Psoriasis Area Severity Index (PASI) (d) (mCherry n = 11, hM3Dq n = 7 mice in a-d). Two-way ANOVA in a: time F(3.252, 52.94) = 99.42, p < 0.0001; mice group F(1, 16) = 28.53, p < 0.0001; interaction F(5, 80) = 11.3, p < 0.0001. Two-way ANOVA in b: time F(2.879, 46.06) = 76.15, p < 0.0001; mice group F(1, 16) = 122.7, p < 0.0001; interaction F(5, 80) = 19.76, p < 0.0001. Two-way ANOVA in c: time F(2.383, 54.12) = 260.2, p < 0.0001; mice group F(1, 16) = 76.82, p < 0.0001; interaction F(5, 80) = 30.12, p < 0.0001. Two-way ANOVA in d: time F(3.68, 58.88) = 336.8, p < 0.0001; mice group F(1, 16) = 179.6, p < 0.0001; interaction F(5, 80) = 50.28, p < 0.0001. e, Representative hematoxylin and eosin staining of skin sections. The epidermis is marked with arrows and dashed lines. f, Calculated epidermal thickness. g-j, Continuous activation of CAVLM neurons suppressed the DTH response. g, Changes in paw thickness 24 hours after injection of mBSA or PBS. mBSA was injected into the footpad of the right hind limb (R_mBSA), whereas PBS was injected into the footpad of the left hind limb (L_PBS). h, i, T-cell proliferation (h) and differentiation (i) in the spleen of DbhVLM-hM3Dq and DbhVLM-mCherry mice 24 hours after injection of mBSA. j, Plasma levels of IFNγ and IL17A 24 hours after injection of mBSA. Each symbol represents an biologically independent samples in g-i. Mice received CNO injection once daily after immunization until study termination. Mean ± s.e.m. Two-sided unpaired t-test in f-j.

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Extended Data Fig. 10 Model of neuronal regulation of the immune system during fasting.

Orexigenic CAVLM neurons are activated during fasting, whose activation stimulates the release of glucocorticoids via the CAVLM→CRHPVN neural circuit targeting the adrenal glands, thereby driving T-cell homing to the bone marrow in a CXCR4CXCL12 axis-dependent manner and suppressing autoimmune diseases.

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Wang, L., Cheng, M., Wang, Y. et al. Fasting-activated ventrolateral medulla neurons regulate T cell homing and suppress autoimmune disease in mice. Nat Neurosci 27, 462–470 (2024). https://doi.org/10.1038/s41593-023-01543-w

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