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Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis

Nature Immunology volume 16, pages 525–533 (2015)Cite this article

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Abstract

Innate immunological signals induced by pathogen- and/or damage-associated molecular patterns are essential for adaptive immune responses, but it is unclear if the brain has a role in this process. Here we found that while the abundance of tumor-necrosis factor (TNF) quickly increased in the brain of mice following bacterial infection, intra-brain delivery of TNF mimicked bacterial infection to rapidly increase the number of peripheral lymphocytes, especially in the spleen and fat. Studies of various mouse models revealed that hypothalamic responses to TNF were accountable for this increase in peripheral lymphocytes in response to bacterial infection. Finally, we found that hypothalamic induction of lipolysis mediated the brain's action in promoting this increase in the peripheral adaptive immune response. Thus, the brain-fat axis is important for rapid linkage of innate immunity to adaptive immunity.

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Figure 1: Central injection of TNF rapidly increases the abundance of splenic and adipose lymphocytes.
Figure 2: The bacterial infection–induced adaptive immune response requires brain TNF.
Figure 3: Hypothalamic TNFRs are required for the adaptive immune response to infection.
Figure 4: Hypothalamic restoration of TNFRs improves adaptive immunity in TNFR-null mice.
Figure 5: Central induction of lipolysis mediates initiation of the adaptive immune response.
Figure 6: Inhibition of fatty acids attenuates brain TNF– or infection-induced adaptive immunity.
Figure 7: Acute effect of the brain-fat axis on adaptive immunity is mediated by adipose nerves.
Figure 8: Chronic neuroinflammation desensitizes the central regulation of adaptive immunity.

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Acknowledgements

We thank the members of the laboratory of D.C. for technical assistance. Supported by the US National Institutes of Health (R01 DK078750, R01 AG031774, R01 HL113180 and R01 DK 099136 to D.C.).

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Authors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA

    Min Soo Kim, Jingqi Yan, Wenhe Wu, Guo Zhang, Yalin Zhang & Dongsheng Cai

  2. Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA

    Min Soo Kim, Jingqi Yan, Wenhe Wu, Guo Zhang, Yalin Zhang & Dongsheng Cai

  3. Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA

    Min Soo Kim, Jingqi Yan, Wenhe Wu, Guo Zhang, Yalin Zhang & Dongsheng Cai

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Contributions

M.S.K. co-designed and performed all experiments, prepared all figures and provided writing assistance; J.Y. did viral injection, histology and immunostaining; W.W. contributed to animal generation, sample preparation and flow cytometry; G.Z. co-designed and did preliminary experiments for Figures 1 and 7; Y.Z. did viral cloning and generated viruses; M.S.K. and D.C. performed data analysis; D.C. conceived of the hypothesis and designed the project and structure of experiments and wrote the paper; and all authors participated in discussions.

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Correspondence to Dongsheng Cai.

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Integrated supplementary information

Supplementary Figure 1 CSF TNF concentrations and hypothalamic TNFR1 distribution.

(a) C57BL/6 mice were intravenously infected with Listeria monocytogenes (LM, +) vs. vehicle (–), and CSF samples were collected at Day 1 vs. 3 post infection for measuring TNF concentrations. (b) TNFR1 immunostaining (green) in the hypothalamus. The arcuate nucleus (ARC) and the medial ventral nucleus (VMH) were delineated. DAPI staining (blue) was used to reveal all cells in tissue sections. 3V: third ventricle. Images represent 3–4 mice per group. Scale bar = 500 μm. (c) Standard C57BL/6 mice were injected via pre-implanted third-ventricle cannula with a single dose (10 pg) of TNF, and CSF samples were collected at indicated time post injection for measuring TNF concentrations. ***P < 0.001 (ANOVA and Tukey’s post-hoc test); n = 5–6 mice per group. All results (mean) reflect two or three independent experiments with similar results (error bars, s.e.m.).

Supplementary Figure 2 Quantification of cell types of the immune system in mice after central injection of TNF or in mice during early bacterial infection.

C57BL/6 mice received daily injections of TNF (10 pg) (+) vs. vehicle (–) in the hypothalamic third-ventricle for 3 days, and then tissues were harvested for flow cytometry. Data show the numbers of F4/80+CD11c+ per gram of epididymal fat (a), spleen (b) and blood (c). Standard C57BL/6 mice were intravenously injected with Listeria monocytogenes (LM, +) vs. vehicle (–), and tissues were harvested at Day 1 or 3 for flow cytometry. Data show numbers of T cells (CD3+) (d,h), CD4+ T cells (CD3+CD4+) (e,i), CD8+ T cells (CD3+CD8+) (f,j) and B cells (B220+) (g,k) per gram of spleen (d–g) and epididymal fat (h–k). **P < 0.01, ***P < 0.001 (ANOVA and Tukey’s post-hoc test); n = 6–8 mice per group. All results (mean) reflect at least three independent experiments with similar results (error bars, s.e.m.).

Supplementary Figure 3 Effects of central injection of TNF on circulating lymphocytes or tissue T cell subtypes.

C57BL/6 mice received daily injections of TNF (10 pg) (+) vs. vehicle (–) in the hypothalamic third-ventricle for 3 days, and tissues were then harvested for flow cytometry. (a–d) Numbers of T cells (CD3+) (a), CD4+ T cells (CD3+CD4+) (b), CD8+ T cells (CD3+CD8+) (c) and B cells (B220+) (d) per gram of blood (n = 6–8 mice per group). (e–n) Numbers of ICOS+PD-1+ (e,g) and PD-L1+ (f,h) per gram of spleen (e,f) and epididymal fat (g,h), and numbers of CXCR3+CD4+CD3+ (i,l), CXCR3-CD4+CD3+ (j,m) and CCR6+CD4+CD3+ (k,n) per gram of spleen (i–k) and epididymal fat (l–n) (n = 4–6 mice per group). *P < 0.05, **P < 0.01 (two-tailed Student’s t-test); All results (mean) reflect two to three independent experiments with similar results (error bars, s.e.m.).

Supplementary Figure 4 Adaptive immune response or function by TNFRs in the hypothalamus and comprised Pomc neurons.

(a–d) Pomc-Cre mice received bilateral MBH injections with Cre-dependent lentiviral TNFR1 shRNA and TNFR2 shRNA (these mice are labeled as Pomc). Wild-type mice received bilateral MBH injections of lentiviral control were used for comparisons (these mice are labeled as WT). All these mice were injected with 10 pg TNF (+) via hypothalamic third-ventricle for 3 days. WT mice receiving vehicle injection in the hypothalamic third ventricle without viral injection (–) were used to provide the basal reference. Tissues were collected for flow cytometry. Data show numbers of T cells (CD3+) (a), CD4+ T cells (CD3+CD4+) (b), CD8+ T cells (CD3+CD8+) (c) and B cells (B220+) (d) per gram of epididymal fat (n = 3–5 mice per group). (e–g) TNFR-null (Tnfr-/-) mice vs. WT containing lentiviral TNFR1 (LV-T) or lentiviral control (LV-C) in the MBH received an intravenous injection of Listeria monocytogenes (LM, +) as described in Fig. 4, and were sacrificed at 3 days post LM injection for counting colony forming unit (CFU) in the spleen (e), epididymal fat (f) and liver (g) (n = 4–7 mice per group). *P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA and Tukey’s post-hoc test); All results (mean) reflect two to three independent experiments with similar results (error bars, s.e.m.).

Supplementary Figure 5 Effects of central injection of TNF or bacterial infection on the release of fatty acids and leptin.

(a) Serum unconjugated fatty acids were measured for mice infected with Listeria monocytogenes (LM) or mice that received hypothalamic third-ventricle injection of TNF (10 pg) (T) or vehicle (V) as described in Figs. 1 and 2. Data represent n = 6–8 mice per group. (b–e) Standard C57BL/6 mice received TNF (10 pg) (+) vs. vehicle (–) injection in the third ventricle (b) as described in Fig. 1, or were intravenously injected with bacteria LM (+) vs. vehicle (–) (c), or co-treated with TNF antagonist WP9QY (W) and LM (+) vs. vehicle (–) injection (c,d) as described in Fig. 2, or injected with lentiviral TNFR1 and TNFR2 shRNA (T-s) vs. lentiviral nontargeting (scramble) shRNA (C-s) with LM (+) or without LM (–) infection (e), and following these treatments at the same time points as described in Fig. 1 to 3, blood samples were collected for measuring serum concentrations of leptin (n = 5 mice per group). *P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA and Tukey’s post-hoc test); All results (mean) reflect two to three independent experiments with similar results (error bars, s.e.m.).

Supplementary Figure 6 Lipolysis mediates the effects of leptin on lymphocytes.

C57BL/6 mice were intraperitoneally pre-injected with cerulenin (Cer) (+) vs. vehicle (–) on the day before other treatments, and then this treatment continued daily for 3 d together with daily intraperitoneal injections of leptin (1.0 mg/kg) (Lep) (+) or vehicle (–), before tissues were harvested for flow cytometry. Data show numbers of T cells (CD3+) (a,e), CD4+ T cells (CD3+CD4+) (b,f), CD8+ T cells (CD3+CD8+) (c,g) and B cells (B220+) (d,h) per gram of epididymal fat (a–d) and spleen (e–h). *P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA and Tukey’s post-hoc test); n = 4–5 mice per group. All results (mean) reflect two to three independent experiments with similar results (error bars, s.e.m.).

Supplementary Figure 7 Coordination of palmitate and leptin in increasing lymphocytes.

C57BL/6 mice were intravenously injected with leptin neutralizing antibody (2.5 mg/kg) (Ab) (+) vs. vehicle (–), and from day 2, they received daily intraperitoneal injections of palmitic acid (PA) (+) or vehicle (–) for 3 d before tissues were harvested for flow cytometry. Data show numbers of T cells (CD3+) (a,e), CD4+ T cells (CD3+CD4+) (b,f), CD8+ T cells (CD3+CD8+) (c,g) and B cells (B220+) (d,h) per gram of epididymal fat (a–d) and spleen (e–h). *P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA and Tukey’s post-hoc test); n = 4–5 mice per group. Results (mean) reflect two to three independent experiments with similar results (error bars, s.e.m.).

Supplementary Figure 8 Conceptual model of this study.

Brain action of TNF is required to initiate the increases of peripheral lymphocytes, and this effect is mediated critically by hypothalamic TNF pathway. This function of hypothalamic TNF in initiating adaptive immunity is induced through hypothalamus-induced lipolysis in cooperation with release of other adipose factors such as leptin. These understanding suggest a conceptual point that the hypothalamus–fat axis plays a role in rapidly linking innate immune signal to adaptive immune responses.

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Kim, M., Yan, J., Wu, W. et al. Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis. Nat Immunol 16, 525–533 (2015). https://doi.org/10.1038/ni.3133

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