Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.

1.1. General overview
The strategic location of the skin as the barrier between the environment and internal milieu determines its critical function in the preservation of body homeostasis, and ultimately organism survival (Slominski, 2005, Slominski and Wortsman, 2000, Slominski et al., 2000c, Zmijewski and Slominski, 2011). It also exposes skin to numerous pathological agents, processes, and events. Thus, the capability to locally recognize, discriminate and integrate various signals within a highly heterogeneous environment, and to immediately launch appropriate responses, is a vital property of skin (Slominski and Wortsman, 2000). These skin functions are integrated into the skin immune, pigmentary, epidermal and adnexal systems, and are in continuous communication with the systemic immune, neural and endocrine systems (Arck et al., 2006, Slominski, 2009c, Slominski et al., 2004c, Slominski and Wortsman, 2000, Slominski et al., 2007a, Stenn and Paus, 2001).

These fundamental functions results from the location of the skin, which is the largest body’s organ, at the interphase between external and internal environment, requiring development of efficient sensory and effector capabilities to differentially react to changes in external environment. They are represented by inducible production of biologically active compounds (hormones, neurohormones and neurotransmitters) that act both locally and at the systemic levels (Fig. 1).



Figure 1

Skin senses changes in the environment through cutaneous neuroendocrine system, which computes and translates the received information into chemical, physical and biological messengers that regulate global (A and B) and local (B) homeostasis. These signals ...



The skin being continuously exposed to many external biological or environmental factors (acute transfers of solar, thermal or chemical energy), had to evolve optimal mechanism(s) to protect, restore or maintain local and global homeostasis in relation to hostile environment (Slominski et al., 1993b, Slominski and Pawelek, 1998, Slominski and Wortsman, 2000, Slominski et al., 2000c). We have proposed that precise coordination and execution of these responses are mediated by a cutaneous neuroendocrine system, which also is able to reset the body homeostatic adaptation mechanisms (Slominski and Wortsman, 2000). Superimposed on this is the impact of psychological stress on skin physiology and pathology, placed in the context of the bidirectional brain-skin communication (Arck et al., 2006, Slominski, 2005a, Slominski et al., 2008b). To summarize, in reaction to changing external and also internal environment, the skin can generate signals to produce rapid (neural) or slow (humoral or immune) responses at the local and systemic levels (Fig. 1).

Coordination between these local and systemic responses is mediated by the skin neuroendocrine system (Slominski and Wortsman, 2000a), which employs local equivalents of the hypothalamo-pituitary-adrenal axis (HPA) (Slominski et al., 2007a), hypothalamo-pituitary-thyroid (HPT) axis (Pisarchik and Slominski, 2002, van Beek et al., 2008), catecholaminergic (Schallreuter et al., 1997), serotoninergic, melatoninergic (Slominski et al., 2008a, Slominski et al., 2005c), cholinergic (Grando, 2006, Grando et al., 2006), steroidogenic (Slominski et al., 2008b) and secosteroidogenic (Bikle, 2010, Holick, 2003, Slominski et al., 2010) systems (Fig. 2). Given their common embryonic origins, it is not surprising that skin shares numerous mediators with the CNS and endocrine system. Recent research has revealed that skin also harbors a complex opioidogenic (Grando et al., 1995, Slominski et al., 2011c) and canabinnoidogenic (Biro et al., 2009) systems, which role in the maintenance of cutaneous homeostasis is currently being intensively explored.



Figure 2

Skin neuroendocrine system follows the algorithms of classical neuroendocrine or endocrine systems. It also forms a natural platform of signal exchange between internal organs and environment. For this purpose skin cells not only are subjected to neurohormonal ...



In this monograph we will discuss the role of various components of the skin neuroendocrine system in sensing the environment with subsequent regulation of local and global homeostasis with a main focus on the algorithms of classical neuroendocrine axes.

Sensing the Environment: Regulation of Local and Global Homeostasis by the Skin's Neuroendocrine System

// Feifei Qiu 1 , Chun-Ling Liang 1 , Huazhen Liu 1 , Yu-Qun Zeng 2 , Shaozhen Hou 3 , Song Huang 3 , Xiaoping Lai 3 , Zhenhua Dai 1 1 Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences and Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China 2 Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China 3 School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China Correspondence to: Zhenhua Dai, email: zdai2009@outlook.com Keywords: cigarette smoking, immunoregulation, adaptive immunity, and innate immunity Received: September 16, 2016      Accepted: November 12, 2016      Published: November 25, 2016 ABSTRACT Cigarette smoking is associated with numerous diseases and poses a serious challenge to the current healthcare system worldwide. Smoking impacts both innate and adaptive immunity and plays dual roles in regulating immunity by either exacerbation of pathogenic immune responses or attenuation of defensive immunity. Adaptive immune cells affected by smoking mainly include T helper cells (Th1/Th2/Th17), CD4+CD25+ regulatory T cells, CD8+ T cells, B cells and memory T/B lymphocytes while innate immune cells impacted by smoking are mostly DCs, macrophages and NK cells. Complex roles of cigarette smoke have resulted in numerous diseases, including cardiovascular, respiratory and autoimmune diseases, allergies, cancers and transplant rejection etc. Although previous reviews have described the effects of smoking on various diseases and regional immunity associated with specific diseases, a comprehensive and updated review is rarely seen to demonstrate impacts of smoking on general immunity and, especially on major components of immune cells. Here, we aim to systematically and objectively review the influence of smoking on major components of both innate and adaptive immune cells, and summarize cellular and molecular mechanisms underlying effects of cigarette smoking on the immune system. The molecular pathways impacted by cigarette smoking involve NFκB, MAP kinases and histone modification. Further investigations are warranted to understand the exact mechanisms responsible for smoking-mediated immunopathology and to answer lingering questions over why cigarette smoking is always harmful rather than beneficial even though it exerts dual effects on immune responses.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=13613&path%5B%5D=43241

Impacts of cigarette smoking on immune responsiveness: Up and down or upside down?

https://www.gastrojournal.org/article/S0016-5085(09)01456-5/pdf

Serotonin Has a Key Role in Pathogenesis of Experimental Colitis

Neurotransmitters, including catecholamines and serotonin, play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the "fight or flight" response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in GI and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, GI innate immune system, and the microbiome. Furthermore, in pathological states, such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of GI symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal GI physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. J. Cell. Physiol. 232: 2359-2372, 2017. © 2016 Wiley Periodicals, Inc.

Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis.

Nicotine and serotonin modulate the innate and adaptive immune responses and the inflammatory states. Several nicotinic cholinergic and serotonergic receptor subtypes have been characterized in B and T lymphocytes, monocytes, macrophages, and dendritic cells. The use of knockout mice has allowed a better characterization of nicotinic receptors and their role in anti-inflammatory processes in these cells. Cytokines play a crucial role in controlling inflammatory reactions. Nicotine and serotonin have been reported to regulate cytokine release. Cholinergic mechanisms also play an important role in inflammation through endogenous acetylcholine. Nicotine mimics this effect by activating the cholinergic anti-inflammatory pathways. New concepts of reciprocal interactions between nicotine and serotonin are emerging. The role of nicotine as an anti-inflammatory agent has been established, whereas that of serotonin remains more controversial.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0906544

Nicotine and serotonin in immune regulation and inflammatory processes: a perspective

Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na+ absorption, a defective cAMP-dependent Cl− conductance, higher concentrations of Na+, Cl−, K+, and Ca2+ in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca2+ entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.

https://www.pnas.org/content/pnas/110/10/4099.full.pdf

Isabelle Cloëz-Tayarani

Papers

Nicotine and serotonin in immune regulation and inflammatory processes: a perspective

Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure