Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Roosterman, Dirk; Goerge, Tobias; Schneider, Stefan W.; Bunnett, Nigel W.; Steinhoff, Martin

doi:10.1152/physrev.00026.2005

Cited by 556 publications

(578 citation statements)

References 939 publications

(764 reference statements)

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“…Skin-resident immune cells can drive inflammation in the skin by interacting directly with nociceptors (80, 81), but were not definitively extracted by our FACS protocol. Furthermore, fibroblasts, keratinocytes, muscle, and other cells may also be activated by the inflammatory milieu (82,83) to secrete factors that activate or sensitize nociceptors (84,85).…”

Section: Discussionmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

156

135

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Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant-and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G + CD11b + neutrophils and T-cell receptor (TCR) β + T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b + Ly6G − myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2 + Ly6C hi ) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b + Ly6G − myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.pain | inflammation | cytokines | monocytes | macrophages

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Section: Discussionmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

156

135

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“…Lastly, we provide substantiation that the cross talk between neuropeptide expression in skin and DRG is In the skin, neuropeptides comprise a large family of regulatory molecules including tachykinins, CGRP, vasoactive intestinal peptide (VIP), pituitary adenylate cyclaseactivating polypeptide (PACAP), and others. Their important role in skin health and disease has been investigated intensively (latest reviews [35,36]). In this context, a wealth of published data is now available on the role of cutaneous SP.…”

Section: Discussionmentioning

confidence: 99%

Neuronal plasticity of the “brain–skin connection”: stress-triggered up-regulation of neuropeptides in dorsal root ganglia and skin via nerve growth factor-dependent pathways

et al. 2007

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Emerging research indicates that central-nervous stress perception is translated to peripheral tissues such as the skin not only via classical stress hormones but also via neurotrophins and neuropeptides. This can result in neurogenic inflammation, which is likely to contribute to the triggering and/aggravation of immunodermatoses. Although the existence of such a "brain-skin connection" is supported by steadily increasing experimental evidence, it remains unclear to which extent perceived stress affects the sensory "hardwiring" between skin and its afferent neurons in the corresponding dorsal root ganglia (DRG). In this paper, we provide experimental evidence in a murine model of stress (exposure of C57BL/6 mice to sound stress) that stress exposure, or intracutaneous injection of recombinant nerve growth factor (NGF) to mimic the skin's response to stress, up-regulate the percentage of substance P (SP) + or calcitonin gene-related peptide (CGRP) + sensory neurons in skin-innervating DRG. Further, we show that the number of SP + or CGRP + sensory nerve fibers in the dermis of stressed C57BL/6 mice is significantly increased. Finally, we document that neutralization of NGF activity abrogates

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“…The regulatory mechanisms are also very complex and involve a combination of sensory, autonomic, and direct effects, including transmitter release and VSM contractile function. While the initial vasoconstriction is believed to be mainly caused by the release of sympathetic neurotransmitters, there are also nonneurogenic vasodilator and vasoconstrictor components of cold response of unknown origin (15,32).…”

mentioning

confidence: 99%

Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

Johnson¹,

Melanaphy²,

Purse³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

136

137

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Johnson CD, Melanaphy D, Purse A, Stokesberry SA, Dickson P, Zholos AV. Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone. Am J Physiol Heart Circ Physiol 296: H1868 -H1877, 2009. First published April 10, 2009 doi:10.1152/ajpheart.01112.2008.-The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue-and activation statedependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 M). However, both menthol and another agonist icilin (50 M) caused relaxation of vessels precontracted with KCl (60 mM) or the ␣-adrenoceptor agonist phenylephrine (2 M) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca 2ϩ -independent phospholipase A 2 activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either N -nitro-L-arginine methyl ester (L-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 M). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of L-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 A). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.human; rat; artery ION CHANNELS, ESPECIALLY Ca 2ϩ -permeable channels, are of central importance to the control of vascular tone as well as long-term phenotypic remodeling. In recent years, members of the transient receptor potential (TRP) superfamily of cation channels attracted considerable interest as novel nonvoltage gated Ca 2ϩ permeable cation channels, important determinants of vascular function and disease (2, 4, 5, 13). These channels can be constitutively active or acti...

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Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Cited by 556 publications

References 939 publications

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Neuronal plasticity of the “brain–skin connection”: stress-triggered up-regulation of neuropeptides in dorsal root ganglia and skin via nerve growth factor-dependent pathways

Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

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Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Cited by 556 publications

References 939 publications

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

Neuronal plasticity of the “brain–skin connection”: stress-triggered up-regulation of neuropeptides in dorsal root ganglia and skin via nerve growth factor-dependent pathways

Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

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CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity