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

Kim MS, Yan J, Wu W, Zhang G, Zhang Y, Cai D - Nat. Immunol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.

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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Hypothalamic TNF receptor is required for adaptive immune response in infection. Standard C57BL/6 mice were bilaterally injected in the arcuate nucleus (ARC) with lentiviral TNFR1 and TNFR2 shRNA (TNFR1 & TNFR2-s, T-s) vs. nontargeting control shRNA (Control-s, C-s), and after 1-week recovery, these mice were infected with Listeria monocytogenes (LM, +) vs. vehicle (−) via intravenous injection. Control mice that did not receive LM injection were included as basal controls (Ctrl). After 3-day bacterial infection, mice were sacrificed and tissues were harvested for flow cytometry analysis.(a) TNFR1 or TNFR2 immunostaining (green) of the MBH. DAPI staining (blue) was used to reveal all cells in tissue sections. Images represent 3–4 mice per group. Scale bar = 200 μm.(b) Dot plots of T cells (CD3+) and B cells (B220+) in epididymal fat and spleen (SPN). Dot plots represent 5–7 mice per group.(c–j) Numbers of T cells (CD3+) (c,g), CD4+ cells (CD3+CD4+) (d,h), CD8+ cells (CD3+CD8+) (e,i) and B cells (B220+) (f,j) per gram of epididymal fat (c–f) or SPN (g–j).*P < 0.05, **P < 0.01 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group (c–j). All data (mean) represent two independent experiments with similar observations (error bars, s.e.m.).
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Figure 3: Hypothalamic TNF receptor is required for adaptive immune response in infection. Standard C57BL/6 mice were bilaterally injected in the arcuate nucleus (ARC) with lentiviral TNFR1 and TNFR2 shRNA (TNFR1 & TNFR2-s, T-s) vs. nontargeting control shRNA (Control-s, C-s), and after 1-week recovery, these mice were infected with Listeria monocytogenes (LM, +) vs. vehicle (−) via intravenous injection. Control mice that did not receive LM injection were included as basal controls (Ctrl). After 3-day bacterial infection, mice were sacrificed and tissues were harvested for flow cytometry analysis.(a) TNFR1 or TNFR2 immunostaining (green) of the MBH. DAPI staining (blue) was used to reveal all cells in tissue sections. Images represent 3–4 mice per group. Scale bar = 200 μm.(b) Dot plots of T cells (CD3+) and B cells (B220+) in epididymal fat and spleen (SPN). Dot plots represent 5–7 mice per group.(c–j) Numbers of T cells (CD3+) (c,g), CD4+ cells (CD3+CD4+) (d,h), CD8+ cells (CD3+CD8+) (e,i) and B cells (B220+) (f,j) per gram of epididymal fat (c–f) or SPN (g–j).*P < 0.05, **P < 0.01 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group (c–j). All data (mean) represent two independent experiments with similar observations (error bars, s.e.m.).

Mentions: Because the MBH, especially the comprised arcuate nucleus, strongly expresses TNFR1, we reasoned that the MBH is critical for the action of central TNF in increasing peripheral lymphocytes. To test this concept, we examined if blocking TNF receptors in the MBH was sufficient to affect adaptive immune response during L. monocytogenes infection. Using site-specific delivery of lentiviral shRNA as we established previously16, we generated mice with MBH-directed TNF receptor knockdown. In this approach, we knocked down TNFR1 as well as TNFR2 to eliminate possible redundancy between these two isoforms. Expression of TNFR1 and TNFR2 protein in the MBH was reduced by shRNA knockdown (Fig. 3a). These mice and the scramble shRNA-injected control mice received an intravenous injection of L. monocytogenes; at 3 days post-infection, various tissues were collected and subjected to flow cytometry. We found that infection-induced increases in adipose CD4+ T, CD8+ T, and B cells were severely impaired in TNFR knockdown mice, compared to scramble shRNA group (Fig. 3b–f). Knockdown of TNF receptors also significantly impaired the induction of splenic CD4+ T, CD8+ T and B cells by infection (Fig. 3b,g–j). In addition, we generated mice in which TNFR was inhibited in the pro-opiomelanocortin (Pomc) neurons in the MBH, and found that this manipulation reduced the effects of central TNF in increasing adipose CD4+ T, CD8+ T and B cells (Supplementary Fig. 4a–d). Thus, based on the collection of these results, the mediobasal region of the hypothalamus is important in linking brain TNF signal to adaptive immunity.


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

Kim MS, Yan J, Wu W, Zhang G, Zhang Y, Cai D - Nat. Immunol. (2015)

Hypothalamic TNF receptor is required for adaptive immune response in infection. Standard C57BL/6 mice were bilaterally injected in the arcuate nucleus (ARC) with lentiviral TNFR1 and TNFR2 shRNA (TNFR1 & TNFR2-s, T-s) vs. nontargeting control shRNA (Control-s, C-s), and after 1-week recovery, these mice were infected with Listeria monocytogenes (LM, +) vs. vehicle (−) via intravenous injection. Control mice that did not receive LM injection were included as basal controls (Ctrl). After 3-day bacterial infection, mice were sacrificed and tissues were harvested for flow cytometry analysis.(a) TNFR1 or TNFR2 immunostaining (green) of the MBH. DAPI staining (blue) was used to reveal all cells in tissue sections. Images represent 3–4 mice per group. Scale bar = 200 μm.(b) Dot plots of T cells (CD3+) and B cells (B220+) in epididymal fat and spleen (SPN). Dot plots represent 5–7 mice per group.(c–j) Numbers of T cells (CD3+) (c,g), CD4+ cells (CD3+CD4+) (d,h), CD8+ cells (CD3+CD8+) (e,i) and B cells (B220+) (f,j) per gram of epididymal fat (c–f) or SPN (g–j).*P < 0.05, **P < 0.01 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group (c–j). All data (mean) represent two independent experiments with similar observations (error bars, s.e.m.).
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Related In: Results  -  Collection

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Figure 3: Hypothalamic TNF receptor is required for adaptive immune response in infection. Standard C57BL/6 mice were bilaterally injected in the arcuate nucleus (ARC) with lentiviral TNFR1 and TNFR2 shRNA (TNFR1 & TNFR2-s, T-s) vs. nontargeting control shRNA (Control-s, C-s), and after 1-week recovery, these mice were infected with Listeria monocytogenes (LM, +) vs. vehicle (−) via intravenous injection. Control mice that did not receive LM injection were included as basal controls (Ctrl). After 3-day bacterial infection, mice were sacrificed and tissues were harvested for flow cytometry analysis.(a) TNFR1 or TNFR2 immunostaining (green) of the MBH. DAPI staining (blue) was used to reveal all cells in tissue sections. Images represent 3–4 mice per group. Scale bar = 200 μm.(b) Dot plots of T cells (CD3+) and B cells (B220+) in epididymal fat and spleen (SPN). Dot plots represent 5–7 mice per group.(c–j) Numbers of T cells (CD3+) (c,g), CD4+ cells (CD3+CD4+) (d,h), CD8+ cells (CD3+CD8+) (e,i) and B cells (B220+) (f,j) per gram of epididymal fat (c–f) or SPN (g–j).*P < 0.05, **P < 0.01 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group (c–j). All data (mean) represent two independent experiments with similar observations (error bars, s.e.m.).
Mentions: Because the MBH, especially the comprised arcuate nucleus, strongly expresses TNFR1, we reasoned that the MBH is critical for the action of central TNF in increasing peripheral lymphocytes. To test this concept, we examined if blocking TNF receptors in the MBH was sufficient to affect adaptive immune response during L. monocytogenes infection. Using site-specific delivery of lentiviral shRNA as we established previously16, we generated mice with MBH-directed TNF receptor knockdown. In this approach, we knocked down TNFR1 as well as TNFR2 to eliminate possible redundancy between these two isoforms. Expression of TNFR1 and TNFR2 protein in the MBH was reduced by shRNA knockdown (Fig. 3a). These mice and the scramble shRNA-injected control mice received an intravenous injection of L. monocytogenes; at 3 days post-infection, various tissues were collected and subjected to flow cytometry. We found that infection-induced increases in adipose CD4+ T, CD8+ T, and B cells were severely impaired in TNFR knockdown mice, compared to scramble shRNA group (Fig. 3b–f). Knockdown of TNF receptors also significantly impaired the induction of splenic CD4+ T, CD8+ T and B cells by infection (Fig. 3b,g–j). In addition, we generated mice in which TNFR was inhibited in the pro-opiomelanocortin (Pomc) neurons in the MBH, and found that this manipulation reduced the effects of central TNF in increasing adipose CD4+ T, CD8+ T and B cells (Supplementary Fig. 4a–d). Thus, based on the collection of these results, the mediobasal region of the hypothalamus is important in linking brain TNF signal to adaptive immunity.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.

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.

Show MeSH
Related in: MedlinePlus