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Abstract
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.
Highlights
The present concept of how peripheral organs engage in a systemic stress response, describes the upregulation of neuronal and non-neuronal neuroendocrine factors in peripheral tissues as a consequence of perceived stress
interleukin 1 beta (IL1β) skin MC (sMC) Expression Is Enhanced by Stress and by Secreted Ly-6/uPAR-related protein 1 (SLURP-1) Under Inflammatory Conditions To learn if SLURP-1 and alpha nicotinic acetylcholine receptor 7 (Chrna7) regulate mast cells (MC)’s cytokine production after stress exposure in addition to the observed MC degranulation, we aimed to identify potential targetcytokines by immunohistochemistry in full thickness skin biopsies from control and 24 h noise stressed mice
To learn more about intermediaries between SLURP-1 and cytokine regulation in MC in response to stress, we studied inflammatory transcription factors focussing on two transcription factors potentially regulated by SLURP-1 and Chrna7: hypoxia inducible factor 1 alpha (HIF1α) [77,78,79] and signal transducer and activator of transcription 3 (STAT3) [80]
Summary
The present concept of how peripheral organs engage in a systemic stress response, describes the upregulation of neuronal and non-neuronal neuroendocrine factors in peripheral tissues as a consequence of perceived stress Along this so called brain-body-axis, neuroendocrine mediators such as cortisol (nor)adrenaline, substance P (SP), or nerve growth factor (NGF) are generated by the activation of systemic stress response systems such as the hypothalamus-pituitary-adrenal axis (HPA), the sympathetic axis (SA) and the sensory nervous system (SNS). They are transported into the peripheral organs via blood vessels or reach them via peripheral autonomic and sensory nerve fibers [1]. If the cholinergic system (CS) and Chrna ligands play a role in these cascades is largely unknown
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