Full length articleGasotransmitters and the immune system: Mode of action and novel therapeutic targets
Introduction
Increasing evidence accumulated during the last decades have shed light into the physiological mechanisms that contribute to down-regulate and turn off immune responses. The endogenous immunomodulators that control responses of both the innate and acquired immune system comprise several and different families of molecules that range from hormones (sex hormones, corticosteroids, D3 vitamin) (Cain and Cidlowski, 2017, Rolf et al., 2016), to endogenous antagonists of cytokines, such as soluble receptors and naturally occurring autoantibodies, and antiinflammatory cytokines of the Th2 and Th3 subtype, including interleukin (IL)-10, IL-13 transforming growth-factor (TGF)-beta and IL-35, proteins such as indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) and heme oxygenase 1 (HO1) and classical immunosuppressive checkpoints, such as cytotoxic T-lymphocyte-associated antigen (CTLA)4 and programmed cell-death protein (PD)1 and PD2 (Gérard et al., 1993, Nicoletti et al., 1997, Bendtzen et al., 2000, Dujmovic et al., 2009, Mackern-Oberti et al., 2014, Meager and Wadhwa, 2014, Raphael et al., 2015, Mbongue et al., 2015, Sakkas et al., 2018, Tocheva and Mor, 2017).
It has been shown that deregulated production of these naturally occurring immunosuppressive and anti-inflammatory mediators, for example due to genetic polymorphisms, may contribute to the development of immunoinflammatory and autoimmune diseases (Barcellini et al., 1996, Arend, 2002).
More recent evidence has shown that additional regulation of immune responses is mediated by a family of gases normally produced in the body such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO) reviewed in (Motterlini and Otterbein, 2010, Wallace et al., 2015, Wallace and Wang, 2015).
These gases are collectively termed as gasotransmitters and are characterized by high lipid solubility and ability of diffusing across cell membranes without the requirement of specific receptors or transporters (Wang, 2014). Gasotransmitters are produced endogenously by specific enzymes and mediate several physiological functions through specific molecular targets (Fig. 1). NO was the first identified gasotransmitter. Using L-arginine as substrate, four isoforms of NO synthases catalyze NO production (Wang, 2014). NO is known as an endothelium-derived relaxing factor (Wang, 2014). As a product of heme metabolism, CO represents another gasotransmitter whose function is partly similar to NO (Wang, 2014). Among several other effects, CO relaxes vascular vessels lowers blood pressure, and protects from ischemia/reperfusion damage (Wang, 2014). Hydrogen sulfide (H2S) is the third gasotransmitter discovered and plays an important role in regulating neurotransmission and neuromodulation (Wang, 2014). Production and metabolism of these molecules are involved in the regulation of diverse biological processes, including vascular tone, immune function, cell survival, metabolism, and stress response (Wang, 2014). Considerable progress has been made in recent years in the pharmacology of NO, CO and H2S with the development of several NO-, CO- and H2S -donors, that have successfully been used in the preclinical setting for the treatment of diverse immunoinflammatory and autoimmune diseases. In recent years, the understanding of the role of gasotransmitters in the immune system has grown significantly, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune cell types, as well as on preclinical models of immunoinflammatory and autoimmune diseases. However, the information are often scattered and partial. This review, therefore, aims at integrating the knowledge in this field emphasizing current evidence supporting the use of gasotransmitters in the clinical setting.
Section snippets
Physiology of carbon monoxide
In mammals, CO is physiologically produced during heme metabolism in the phagocytic system of the spleen and liver. The process is catalyzed by HO enzymes, encoded by the HMOX genes. In the presence of HO enzymes, the porphyrin ring of heme is oxidized and equimolar amounts of CO, ferrous iron and biliverdin are produced. Three isoforms of HO, HO-1, HO-2 and HO-3 are currently characterized. HO-1 is the inducible isoform and its transcriptional levels increase following cellular stress. On the
Biology of nitric oxide
In eukariotic cells, NO is mainly synthesized from L-arginine by three different enzymes, the neuronal (nNOS), inducible (iNOS) and endothelial (eNOS) nitric oxide synthase. These enzymes contain an oxigenase domain at the Nterminal, a reductase domain at the Cterminal, and a calmodulin binding region between the two (Smith et al., 2013). The nNOS and eNOS enzymes are constitutively expressed among several cell types, including endothelial cells, platelets, and neurons. They have a much
Hydrogen sulfide biology
H2S is a colourless, water-soluble, gas with a smell like rotten egg. Although considered as a toxic gas and an environmental hazard, it is produced in substantial quantities in mammalian tissues and it can be detected at significant levels (Szabó, 2007). H2S production is catalyzed by two pyridoxal phosphate-dependent enzymes, cystathionine b-synthase (CBS) and cystathionine g-lyase (CSE) that use the amino acids cysteine, homocysteine and cystathionine as substrates (Szabó, 2007). H2S is
A new class of molecules: nitric oxide–hydrogen sulfide-releasing hybrids
Based on the encouraging data coming from the NO-NSAID and S-NSAID, it was more recently proposed that an NSAID releasing both NO and H2S could be more potent than either one of the two. This was followed by the development of four NOSH molecules having aspirin as scaffold. Nitrate (-ONO) was used as NO-donating moiety and linked to the aspirin through an aliphatic spacer, while either 5-(4-hydroxyphenyl)-3H-1, 2-dithiole-3-thione (ADTOH), or 4-hydroxy benzothiazamide (TBZ) or lipoic acid were
Conclusions
Research on gasotransmitters is growing and knowledge about the potential of gasotransmitters in physiology and pathology is rapidly accumulating. It is clear that gasotransmitters represent key players in both health and diseases. From the accumulated data, it appears as gasotransmitters represent key effectors in both innate and adaptive immune responses. Moreover, the encouraging results from preclinical animal models provide the basis for therapeutic approaches of infectious, autoimmune,
Acknowledgment
This study was supported by current research funds 2016 of IRCCS "Centro Neurolesi "Bonino Pulejo"", Messina-Italy.
Author disclosure statement
Paolo Fagone, Emanuela Mazzon, Placido Bramanti and Klaus Bendtzen do not declare any competing financial interests. Ferdinando Nicoletti is cofounder and shareholder of OncoNox that has patent on composition of matter and use of Saquinavir-NO.
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