title: Toll-like receptors 2 and 4 modulate autonomic control of heart rate and energy metabolism.
abstract: Toll-like receptors (TLR) are innate immune receptors typically activated by microbial-associated molecular patterns (MAMPs) during infection or damage-associated molecular patterns (DAMPs) as a result of tissue injury. Recent findings suggest that TLR2 and TLR4 signaling play important roles in developmental and adult neuroplasticity, and in learning and memory. In addition, activation of TLR2 and TLR4 worsens ischemic injury to the heart and brain in animal models of myocardial infarction and stroke. TLR activation is also implicated in thermoregulation and fever in response to infection. However, it is not known whether TLRs participate in the regulation of the sympathetic and/or parasympathetic components of the autonomic nervous system (ANS). Here we provide evidence that TLR2 and TLR4 influence autonomic regulation of heart rate (HR) body temperature and energy metabolism in mice. We show that mice lacking TLR2 or TLR4 exhibit reduced basal HR, which results from an increase of parasympathetic tone. In addition, thermoregulatory responses to stress are altered in TLR2-/- and TLR4-/- mice, and brown fat-dependent thermoregulation is altered in TLR4-/- mice. Moreover, TLR2-/- and TLR4-/- mice consume less food and exhibit a greater mass compared to wild type mice. Collectively, our findings suggest important roles for TLR2 and TLR4 in the ANS regulation of cardiovascular function, thermoregulation, and energy metabolism.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel. Electronic address: eitan.okun@biu.ac.il.
authors.forename: Eitan
authors.initials: E
authors.lastname: Okun
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Griffioen
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rothman
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Ruiqian
authors.initials: R
authors.lastname: Wan
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Cong
authors.affiliation: Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: De Cabo
authors.affiliation: Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martin-Montalvo
authors.affiliation: Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Levette
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.affiliation: Department of Neurology, The University of Queensland, St. Lucia, Queensland 4067, Australia.
authors.forename: Thiruma Valavan
authors.initials: TV
authors.lastname: Arumugam
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA; School of Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D001831:Body Temperature; D001833:Body Temperature Regulation / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: ANS; Autonomic nervous system; Heart rate; Innate immunity; Stress; TLR2; TLR4; Toll-like receptors