Limits...
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.

Show MeSH

Related in: MedlinePlus

Fatty acid inhibition attenuates brain TNF- or infection-induced adaptive immunity. Standard C57BL/6 mice received an i.p. injection of cerulenin (Cer, +) vs. vehicle saline (−) on the day prior to other treatments (a–p), followed by daily hypothalamic third-ventricle injections of 10 pg TNF (+) vs. vehicle aCSF (−) together with daily i.p. injections of cerulenin for 3 days (a–h), or followed by a single intravenous injection of Listeria monocytogenes (LM, +) vs. the vehicle (−) while daily i.p. injections of cerulenin continued for 3 days (i–p). Following these treatments, tissues were harvested and subjected to flow cytometry analysis. Data show numbers of T cells (CD3+) (a,e,i,m), CD4+ cells (CD3+ CD4+) (b,f,j,n), CD8+ cells (CD3+ CD8+) (c,g,k,o) and B cells (B220+) (d,h,l,p) per gram of epididymal fat (a–d,i–l) or spleen (SPN) (e–h,m–p) in TNF-injected (a–h) or LM-infected mice (i–p).*P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group. All data (mean) represent at least three independent experiments with similar observations (error bars, s.e.m.).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4564120&req=5

Figure 6: Fatty acid inhibition attenuates brain TNF- or infection-induced adaptive immunity. Standard C57BL/6 mice received an i.p. injection of cerulenin (Cer, +) vs. vehicle saline (−) on the day prior to other treatments (a–p), followed by daily hypothalamic third-ventricle injections of 10 pg TNF (+) vs. vehicle aCSF (−) together with daily i.p. injections of cerulenin for 3 days (a–h), or followed by a single intravenous injection of Listeria monocytogenes (LM, +) vs. the vehicle (−) while daily i.p. injections of cerulenin continued for 3 days (i–p). Following these treatments, tissues were harvested and subjected to flow cytometry analysis. Data show numbers of T cells (CD3+) (a,e,i,m), CD4+ cells (CD3+ CD4+) (b,f,j,n), CD8+ cells (CD3+ CD8+) (c,g,k,o) and B cells (B220+) (d,h,l,p) per gram of epididymal fat (a–d,i–l) or spleen (SPN) (e–h,m–p) in TNF-injected (a–h) or LM-infected mice (i–p).*P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group. All data (mean) represent at least three independent experiments with similar observations (error bars, s.e.m.).

Mentions: Loss-of-function experiments were simultaneously developed to study if fatty acids could be inhibited to cause an impaired effect of brain TNF in stimulating adaptive immunity. In these experiments, we i.p. injected C57BL/6 mice with a fatty acid synthase inhibitor, cerulenin, at the dose of 10 mg/kg/day for 3 days before these mice received daily hypothalamic third-ventricle injections of TNF (10 pg). While lymphocyte numbers in the fat of these mice increased by the central injection of TNF, these changes in the fat were completely prevented by cerulenin pre-treatment (Fig. 6a–d). Notably the effects of central TNF in increasing splenic T and B cells were also abolished by cerulenin pre-treatment (Fig. 6e–h), suggesting that release of fatty acids from the fat has an effect in initiating the increase of splenic lymphocytes.


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)

Fatty acid inhibition attenuates brain TNF- or infection-induced adaptive immunity. Standard C57BL/6 mice received an i.p. injection of cerulenin (Cer, +) vs. vehicle saline (−) on the day prior to other treatments (a–p), followed by daily hypothalamic third-ventricle injections of 10 pg TNF (+) vs. vehicle aCSF (−) together with daily i.p. injections of cerulenin for 3 days (a–h), or followed by a single intravenous injection of Listeria monocytogenes (LM, +) vs. the vehicle (−) while daily i.p. injections of cerulenin continued for 3 days (i–p). Following these treatments, tissues were harvested and subjected to flow cytometry analysis. Data show numbers of T cells (CD3+) (a,e,i,m), CD4+ cells (CD3+ CD4+) (b,f,j,n), CD8+ cells (CD3+ CD8+) (c,g,k,o) and B cells (B220+) (d,h,l,p) per gram of epididymal fat (a–d,i–l) or spleen (SPN) (e–h,m–p) in TNF-injected (a–h) or LM-infected mice (i–p).*P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group. All data (mean) represent at least three independent experiments with similar observations (error bars, s.e.m.).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4564120&req=5

Figure 6: Fatty acid inhibition attenuates brain TNF- or infection-induced adaptive immunity. Standard C57BL/6 mice received an i.p. injection of cerulenin (Cer, +) vs. vehicle saline (−) on the day prior to other treatments (a–p), followed by daily hypothalamic third-ventricle injections of 10 pg TNF (+) vs. vehicle aCSF (−) together with daily i.p. injections of cerulenin for 3 days (a–h), or followed by a single intravenous injection of Listeria monocytogenes (LM, +) vs. the vehicle (−) while daily i.p. injections of cerulenin continued for 3 days (i–p). Following these treatments, tissues were harvested and subjected to flow cytometry analysis. Data show numbers of T cells (CD3+) (a,e,i,m), CD4+ cells (CD3+ CD4+) (b,f,j,n), CD8+ cells (CD3+ CD8+) (c,g,k,o) and B cells (B220+) (d,h,l,p) per gram of epididymal fat (a–d,i–l) or spleen (SPN) (e–h,m–p) in TNF-injected (a–h) or LM-infected mice (i–p).*P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA, Tukey's post-hoc); n = 5–7 mice per group. All data (mean) represent at least three independent experiments with similar observations (error bars, s.e.m.).
Mentions: Loss-of-function experiments were simultaneously developed to study if fatty acids could be inhibited to cause an impaired effect of brain TNF in stimulating adaptive immunity. In these experiments, we i.p. injected C57BL/6 mice with a fatty acid synthase inhibitor, cerulenin, at the dose of 10 mg/kg/day for 3 days before these mice received daily hypothalamic third-ventricle injections of TNF (10 pg). While lymphocyte numbers in the fat of these mice increased by the central injection of TNF, these changes in the fat were completely prevented by cerulenin pre-treatment (Fig. 6a–d). Notably the effects of central TNF in increasing splenic T and B cells were also abolished by cerulenin pre-treatment (Fig. 6e–h), suggesting that release of fatty acids from the fat has an effect in initiating the increase of splenic lymphocytes.

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