Gasotransmitters and the immune system: Mode of action and novel therapeutic targets

Abstract

Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H₂S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the immune system has grown significantly in the past years, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune responses. Moreover, encouraging results come from the efficacy of NO-, CO- and H₂S -donors in preclinical animal models of autoimmune, acute and chronic inflammatory diseases. To date, data on the influence of gasotransmitters in immunity and immunopathology are often scattered and partial, and the scarcity of clinical trials using NO-, CO- and H₂S -donors, reveals that more effort is warranted. This review focuses on the role of gasotransmitters in the immune system and covers the evidences on the possible use of gasotransmitters for the treatment of inflammatory conditions.

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.