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170222 Bergin Dissertation.pdf (3.77 MB)

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Hypothalamic brain-derived neurotrophic factor regulates lymphocyte immunity, energy balance, and cancer progression

Bergin, Stephen Michael
http://orcid.org/0000-0001-9692-5814
http://rave.ohiolink.edu/etdc/view?acc_num=osu1487669797216355

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Macro-environmental factors, including a patient’s physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTLs). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT suggesting both the sympathetic nervous system and hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Environmental and social factors are profound determinants of metabolic health and impact immune homeostasis. Here we investigated how EE housing activates a brain-adipocyte axis to coordinate the adipose immune microenvironment. EE housing induces expression of hypothalamic BDNF, which increases sympathetic innervation to adipose tissue and results in early accumulation of classical-Natural Killer (cNK) cells. The EE-induced increase of adipose cNK cells occurred when mice were fed a normal-chow but was eliminated when fed a high-fat diet. Our mechanistic studies demonstrated that this hypothalamic-sympathoneural-adipocyte axis increases adipocyte gene expression of IL-15, which, if blocked, eliminates the accumulation of adipose-cNKs. Interrogation of ß-adrenergic signaling revealed a ß3-receptor pathway, which increased cNKs in association with increase adipocyte IL-15. These results demonstrate how environmental intervention, acting through a single gene in the brain, regulates adipose cNKs.
Michael Caligiuri, M.D. (Advisor)
Lei Cao, Ph.D. (Committee Member)
Jianhua Yu, Ph.D. (Committee Member)
110 p.
Immunology
immunology; innate lymphocytes; natural killer cell; adipocyte; adipose tissue; cancer progression; psychoneuroimmunology; brain-immune; stress; enriched environment; BDNF; hypothalamus

Recommended Citations

Citations

  • Bergin, S. M. (2017). Hypothalamic brain-derived neurotrophic factor regulates lymphocyte immunity, energy balance, and cancer progression [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487669797216355

    APA Style (7th edition)

  • Bergin, Stephen. Hypothalamic brain-derived neurotrophic factor regulates lymphocyte immunity, energy balance, and cancer progression. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1487669797216355.

    MLA Style (8th edition)

  • Bergin, Stephen. "Hypothalamic brain-derived neurotrophic factor regulates lymphocyte immunity, energy balance, and cancer progression." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487669797216355

    Chicago Manual of Style (17th edition)

osu1487669797216355
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This open access ETD is published by The Ohio State University and OhioLINK.