Review
Is lipid signaling through cannabinoid 2 receptors part of a protective system?

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Abstract

The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects.

Introduction

The mammalian body has a highly developed immune system, whose main role is to guard against protein attack and prevent, reduce or repair a possible injury. It is inconceivable that through evolution analogous biological protective systems have not been developed against non-protein attacks. Are there mechanisms through which our body lowers the damage caused by various types of neuronal as well as non-neuronal insults? The answer is of course positive. Through evolution numerous protective mechanisms have been evolved to prevent and limit tissue injury.

We believe that lipid signaling through cannabinoid 2 (CB2) receptors is a part of such a protective machinery and CB2 receptor stimulation leads mostly to sequences of activities of a protective nature. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate fast signaling responses in immune and other cells modulating their critical functions. Endocannabinoids and endocannabinoid-like molecules acting through the CB2 cannabinoid receptor have been reported to affect a large number of pathological conditions, ranging from cardiovascular [1], [2], gastrointestinal [3], [4], liver [5], [6], [7], kidney [8], [9], lung [10], neurodegenerative [11], [12], [13], [14] and psychiatric [15], [16], [17], [18], [19], [20] disorders to pain [21], [22], cancer [23], [24], [25], [26], bone [27], [28], reproductive system [29], [30], [31] and skin pathologies [32] (Fig. 1). This receptor works in conjunction with the immune system and with various other physiological systems. As numerous excellent reviews have been published on the actions of the endocannabinoid system on specific topics, in this Review we aim to summarize some of the protective actions of the CB2 receptor stimulation with endocannabinoids or synthetic agonists, and the possibly biological mechanisms involved in these effects. While CB2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions.

Section snippets

The endocannabinoid system and endocannabinoids

The endocannabinoid system is a latecomer to the family of neuromodulators. Looking back, its late discovery was an anomaly. Despite the advances made in the chemistry of cannabinoids, the molecular basis of cannabinoid activity remained enigmatic for several decades. The chemistry of the constituents of the cannabis plant was investigated from the mid 19th century intermittently for almost a century [33], but the main psychoactive constituent, Δ9-tetrahydrocannabinol (THC), was isolated in

CB2 receptors and endocannabinoids in health and disease

The CB2 receptor was previously considered to be expressed predominantly in immune and hematopoietic cells. Indeed, CB2 receptors are expressed in almost all human peripheral blood immune cells with the following rank order of mRNA levels: B cells > NK cells > monocytes > PMNs > T cells, respectively (overviewed in [76]). The CB receptor expression in immune cells can be influenced by various inflammatory, e.g. bacterial lipopolysaccharide (LPS), and other triggers activating these cells, and may

Effects of CB2 receptor modulation in disease states

The significance of CB2 receptor activation in the above mentioned immunomodulatory effects of endocannabinoids and of various cannabinergic ligands is now becoming increasingly recognized, and most likely these effects are largely responsible for the anti-inflammatory properties of endogenous or synthetic ligands observed in a multitude of disparate diseases and pathological conditions, ranging from atherosclerosis, myocardial infarction, stroke, inflammatory pain, gastrointestinal

Conclusions

Overwhelming evidence has established an important role for endocannabinoid-CB2 receptor signaling in a large number of the major pathologies affecting humans. The broad spectrum of actions that can be attributed to CB2 receptor signaling in inflammatory, autoimmune, cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric and many other diseases have been reviewed here in some detail (Fig. 1 and Table 2). Most likely, the primary cellular targets and executors of the CB2

Acknowledgements

This study was supported by the Intramural Research Program of NIH/NIAAA (to P.P.) and by NIDA grant #9789 (to R.M.). The authors are indebted to Dr. George Kunos for providing key resources and support and apologize to colleagues whose important work could not be cited because of the size limitations of this review.

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