Inhibition of the cannabinoid 2 receptor in CNS-injury induced immunodeficiency syndrome
Introduction
Central nervous system (CNS) injury, such as stroke, is known to increase patients’ susceptibility to infections that adversely affect outcome [1]. This concept of infection susceptibility and impaired immune function is referred to as CNS-injury induced immunodeficiency syndrome (CIDS), as both the CNS and the peripheral immune response are thought to collectively contribute to the immunodepression [1].
Modern medicine discovered that CNS injury causes an imbalance in the interplay between the immune system and the CNS, leading to a vulnerable state of systemic immunodeficiency via specific mechanisms. Therefore, patients that have an acute CNS injury, such as traumatic brain injury or stroke are very susceptible to infections. Langhorne et al. observed in a prospective study that up to 85% of stroke patients experience complicating medical events during the phase of acute care [2]. Immune dysfunction is the reason why infections are the leading cause of death in these patients. A series of studies showed decreased natural killer (NK) cell counts and cytotoxic activity in this patient population [3], [4], [5]. In addition, infections prevent and delay neurological recovery, worsening the patient’s outcome, increasing the morbidity as well as mortality. Secondary infections that happens post-CNS injury cause the affected patients to be exposed to additional invasive medical procedures and hospitalizations [6].
The immune system is heavily involved in the reparative processes that follow an acute CNS injury. During, and shortly after the acute CNS injury, the ensuing inflammation that initially occurs may have benefits in terms of activating mechanisms that remove the damaged cells and nervous tissue [1]. There is overwhelming experimental and clinical evidence which confirms that a range of pro-inflammatory genes are upregulated, along with induction of adhesion molecules such as selectins and integrins, activation of the peripheral immune system and activation of microglia in the brain, promoting the expression of pro-inflammatory cytokines such as TNF-α and IL-1 shortly after the acute injury happens [1]. Hug et al. reported a close relationship between the severity of experimental ischemic stroke and the extent of post-stroke immunodepression [7]. The same group observed that while small infarcts led to no significant changes in differential blood count or changes of overall cell counts in lymphatic organs, extensive infarcts induced leukopenia, decreased lymphocytes counts in spleen, thymus and lymph nodes [8].
Experimental and clinical evidence suggests that severe CNS-injury is associated with significant immunological consequences, i.e. systemic inflammatory response immediately following CNS injury [9]. In rodent models and patients with ischemic CNS injury, white blood cell count, plasma levels of pro-inflammatory cytokines and other inflammatory markers are increased within hours after the injury [10], [11], [12], [13]. Being a physiologic response to the local ischemic event, hyper-activation of those pathways may also increase CNS tissue damage [14]. The systemic inflammatory response is therefore countered by induction of localized and generalized anti-inflammatory pathways (immunosuppression) to minimize the secondary damage to CNS, initiating CIDS as a potentially neuroprotective mechanism [6], [9], [15].
The ischemic cell death sets the stage for innate and adaptive immunity [14]. Accordingly, immunodeficiency after stroke affects both systems. Alterations in post-stroke immune suppression include, but may not be limited to inactivation of macrophages, lymphocytopenia and increased serum IL-10 concentrations [15]. Li et al. found that the cytotoxic function of CD8+ T lymphocytes in the peripheral blood of patients with severe cerebral infarction was significantly suppressed, resulting in a decreased rate of degranulated cells and reduced pro-inflammatory cytokine production [16]. Recent animal studies showed that CD8+ T lymphocytes induce neurotoxic effects in the early stage of acute cerebral ischemia. Accordingly, Yilmaz et al. observed that the size of cerebral infarction was distinctly reduced in CD8+ k.o. mice with experimental stroke [17]. The studies by Li et al. and Yilmaz et al. also show, that while it remains important to differentiate between local and peripheral/systemic immunosuppression this separation is essentially removed in severe CNS injury since the blood brain barrier is dysfunctional, leading to exposure of normally isolated and protected brain structural elements.
Proposed potential mechanisms behind CIDS are down-regulation of the immune response via the sympathetic nervous system and the hypothalamic–pituitary axis [8]. Catecholamines and cortisol plasma levels are elevated in patients after stroke most susceptible to infection [18], and steroid antagonists and the β-adrenergic receptor antagonist propranolol counteract lymphocyte apoptosis and infection propensity after stroke in rodent models [19].
The endocannabinoid system (ECS) is composed of two receptors, cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R), endogenous cannabinoid ligands, including anandamide (arachidonic acid ethanolamide or AEA) and 2-arachidonoyl glycerol (2-AG), as well as the enzymes that synthesize and degrade them. Recent investigation into the ECS has demonstrated a variety of important effects both centrally and peripherally within the body. Of these effects, the role of the ECS, and in particular CB2R, in immunomodulation is of specific importance and has been at the forefront of recent investigation.
In addition to developing an effective therapeutic strategy for CIDS, there is also a strong and urgent need to raise awareness about CIDS among health professionals and especially physicians that work with patients with acute CNS injury, to ensure that appropriate therapeutic countermeasures are taken [6].
Section snippets
Hypothesis
Following stroke, the endocannabinoid system, including CB2Rs, is upregulated thereby contributing to the immunosuppression seen in CIDS. In this scenario, while the initial endogenous activation of CB2R post-stroke may be protective in limiting neuroinflammation, protracted CB2R activation may be detrimental during CIDS. Therefore, we hypothesize that inhibition of CB2R in CNS-injury induced immunodeficiency syndrome will reduce post-stroke immunosuppression, providing the patient protection
Discussion
The cannabinoid receptors are G-protein coupled receptors that are linked to Gi and inhibit adenylyl cyclase, thereby decreasing levels of cAMP [20]. These receptors are coupled to multiple secondary messenger systems such as, nitric oxide synthase, Ca channels, phospholipase C, and mitogen activated protein (MAP) kinases, which serve as signaling mechanisms within immune cells [21] and lead to increased activation of p38 and NF-κB [22]. The receptors themselves exist as multiple isoforms in a
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
This work was supported in part by Shriners of North America Grant 85210.
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