New pathways for the skin's stress response: the cholinergic neuropeptide SLURP-1 can activate mast cells and alter cytokine production in mice

  • Background: The alpha7 nicotinic acetylcholine receptor (Chrna7) plays an essential anti-inflammatory role in immune homeostasis and was recently found on mast cells (MC). Psychosocial stress can trigger MC hyperactivation and increases pro-inflammatory cytokines in target tissues such as the skin. If the cholinergic system (CS) and Chrna7 ligands play a role in these cascades is largely unknown. Objective: To elucidate the role of the CS in the response to psychosocial stress using a mouse-model for stress-triggered cutaneous inflammatory circuits. Methods: Key CS markers (ACh, Ch, SLURP-1, SLURP-2, Lynx1, Chrm3, Chrna7, Chrna9, ChAT, VAChT, Oct3, AChE, and BChE) in skin and its MC (sMC), MC activation, immune parameters (TNFα, IL1β, IL10, TGFβ, HIF1α, and STAT3) and oxidative stress were analyzed in skin from 24 h noise-stressed mice and in cultured MC (cMC) from C57BL/6 or Chrna7-Knockout mice. Results: First, Chrna7 and SLURP-1 mRNA were exclusively upregulated in stressed skin. Second, histomorphometry located Chrna7 and SLURP-1 in nerves and sMC and demonstrated upregulated contacts and increased Chrna7+ sMC in stressed skin, while 5 ng/mL SLURP-1 degranulated cMC. Third, IL1β+ sMC were high in stressed skin, and while SLURP-1 alone had no significant effect on cMC cytokines, it upregulated IL1β in cMC from Chrna7-KO and in IL1β-treated wildtype cMC. In addition, HIF1α+ sMC were high in stressed skin and Chrna7-agonist AR-R 17779 induced ROS in cMC while SLURP-1 upregulated TNFα and IL1β in cMC when HIF1α was blocked. Conclusions: These data infer that the CS plays a role in the regulation of stress-sensitive inflammatory responses but may have a surprising pro-inflammatory effect in healthy skin, driving IL1β expression if SLURP-1 is involved.

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Author:Christoph M. Ertle, Frank Risto Rommel, Susanne Tumala, Yasuhiro Moriwaki, Jochen KleinORCiD, Johannes Kruse, Uwe Gieler, Eva M. J. Peters
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Document Type:Article
Date of Publication (online):2021/03/18
Date of first Publication:2021/03/18
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/11/02
Tag:Chrna7 knockout; alpha7 nicotinic acetylcholine receptor; cholinergic system; hypoxia inducible factor 1 alpha; mast cells; secreted Ly-6/uPAR-related protein 1; stress
Issue:art. 631881
Page Number:18
First Page:1
Last Page:18
This study was supported by the Landes-Offensive zur Entwickling Wissenschaftlich-ökonomischer Exzellenz (LOEWE) of the state Hesse Focus Group Non-neuronal cholinergic systems to EP and UG and research support by the Universitätsmedizin-Charité, Berlin, Germany to EP. The founding source was not involved in the study design; the collection, analysis and interpretation of data; writing of the report; or decision to submit the article for publication.
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0