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Modern Aspects of Cutaneous Neurogenic Inflammation

Martin Steinhoff, MD, PhD; Sonja Ständer, MD; Stephan Seeliger, MD; John C. Ansel, MD; Martin Schmelz, MD; Thomas Luger, MD
Arch Dermatol. 2003;139(11):1479-1488. doi:10.1001/archderm.139.11.1479.
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Recent findings have shed new light on the role of peripheral nerves in the skin and established a modern concept of cutaneous neurobiology. Closely related monodirectional and/or bidirectional pathways exist in which the central and peripheral nervous system, the endocrine and immune system, and almost all skin cells are involved. Information is emerging about the factors involved in these immunomodulatory mechanisms, which are defined as neuropeptides, neurotransmitters, neurotrophins, and neurohormones. The interaction between peripheral nerves and the immune system is mediated by different types of cutaneous nerve fibers that release neuromediators and activate specific receptors on target cells in the skin such as keratinocytes, mast cells, Langerhans cells, microvascular endothelial cells, fibroblasts, and infiltrating immune cells. These interactions influence a variety of physiologic and pathophysiologic functions including cellular development, growth, differentiation, immunity, vasoregulation, leukocyte recruitment, pruritus, and wound healing. A variety of mechanisms lead to the termination of cellular responses to released neuropeptides under physiologic circumstances. Herein, we highlight some of the recent advances of neurocutaneous biology and discuss the role of nerves in mediating cutaneous inflammation. Understanding the mechanisms and the factors controlling neuromediators and their receptors and degrading enzymes will lead to the identification of novel therapeutic targets for the treatment of cutaneous diseases.

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Proteinase-activated receptor 2 (PAR-2) regulates inflammation by a neurogenic mechanism: (1) tryptase released from degranulated mast cells cleaves PAR-2 at the plasma membrane of sensory nerve endings to expose a tethered ligand domain that binds and activates the cleaved receptor; (2) activation of PAR-2 stimulates the release of calcitonin gene-related peptide (CGRP) and the tachykinins substance P (SP) and neurokinin A (NK-A) from sensory nerve endings; (3) CGRP interacts with the CGRP-1 receptor to induce arteriolar dilation and hyperanemia; (4) SP interacts with the neurokinin-1 (NK-1) receptor on endothelial cells of postcapillary venules to cause gap formation and plasma extravasation; the hyperanemia and plasma extravasation cause edema; (5) SP may stimulate degranulation of mast cells, providing a positive feedback; (6) tryptase degrades CGRP and terminates its effects; (7) CGRP inhibits SP degradation by neutral endopeptidase and also enhances SP release, thereby amplifying the effects; (8) mediators from mast cells and other inflammatory cells stimulate the release of vasoactive peptides from sensory nerves and also sensitize nerves; (9) in addition to peripheral stimulation of neurogenic inflammation, PAR-2 agonists induce central transmission of pain and pruritus. ATP indicates adenosine triphosphate.

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