Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation

Abstract

Sickness behaviors are host defense adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviors include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) receptor activation can induce hypothermia and attenuate LPS-evoked fever. The aim of the present study was to examine the role of CB1 receptors in the LPS-evoked febrile response. CB1 receptor-deficient (CB1 Ϫ/Ϫ ) mice did not display LPSevoked fever; likewise, pharmacological blockade of CB1 receptors in wild-type mice blocked LPS-evoked fever. This unresponsiveness is not limited to thermogenesis, as the animals were not hyperalgesic after LPS administration. A Toll-like receptor (TLR)3 agonist and viral mimetic polyinosinic:polycytidylic acid evoked a robust fever in CB1 Ϫ/Ϫ mice, suggesting TLR3-mediated responses are functional. LPS-evoked c-Fos activation in areas of the brain associated with the febrile response was evident in wild-type mice but not in CB1 Ϫ/Ϫ mice. Liver and spleen TLR4 mRNA were significantly lower in CB1 Ϫ/Ϫ mice compared with wild-type mice, and peritoneal macrophages from CB1 Ϫ/Ϫ mice did not release proinflammatory cytokines in response to LPS. These data indicate that CB1 receptors play a critical role in LPS-induced febrile responses through inhibiting TLR4-mediated cytokine production.endocannabinoid; Toll-like receptor; fever; cytokine FEVER IS AN IMPORTANT COMPONENT of the innate immune response; subjects that are prevented from developing fever have increased morbidity and mortality (24,30). Fever occurs when structural motifs on bacterial cell walls, e.g., LPS for gramnegative bacteria, or double-stranded viral DNA, are recognized by Toll-like receptors (TLRs) on cells of the innate immune system (2, 32). LPS-evoked inflammation is via TLR4 activation, whereas viral moieties are recognized by TLR3. These signaling pathways are activated in monocytes and circulating or resident macrophages (e.g., Kupffer cells of the liver) to cause synthesis and release of a number of pyrogenic factors, including IL-1, IL-6, TNF-␣, and IFN␥. These cytokines signal to the brain to induce cyclooxygenase (COX) 2-dependent prostaglandin synthesis and additional cytokine synthesis in the brain (11). The resulting thermoregulatory response consists of both hypothermic and hyperthermic components, depending upon pyrogen, dose, and ambient temperature (47) and is often accompanied by other components of the host defense response, including hyperalgesia, anorexia, and sickness behaviors (14). Almost concurrently with the generation of a proinflammatory response is the production of several anti-inflammatory cytokines (e.g., IL-1 receptor antagonist, IL-10) and corticosteroids that limit the febrile response (7,46).Innate immune febrile responses can be modified by endogenous cannabinoids (eCB) acting on cannabinoid receptors (CB 1 and CB 2 ) in the central nervous system and periphery. The best recognized eCBs ar...

Immunoregulatory Role of Cannabinoids during Infectious Disease

“…In the case of infection with L. pneumophila, this effect is due to immune system malfunction, caused by a compromised Th1 protective response [37] or because macrophage functions are inhibited [41], thereby supporting the notion that ECS activation contributes to the function of the immune system. Interestingly, when LPS was injected into mice, the results were similar to the results reported in vitro, because the lack of cannabinoid receptors induced an ineffective immune response [32,33].…”

“…A murine study model involving the injection of LPS is how the role of CB1 and CB2 during sepsis was discovered. Where the activation of CB1 is concerned, this allows the good functioning of innate immunity parameters, e.g., CB1-deficient mice are unable to develop fever, have a lower expression of TLR4 in the liver and spleen when compared to wild-type (WT) mice, and their peritoneal macrophages do not secrete proinflammatory cytokines [32].…”

FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus

“…Although the effects of cannabinoids and endocannabinoid modulators including URB597, on the expression of inflammatory cytokines in the brain following systemic administration of the TLR4 agonist and bacterial endotoxin LPS, has been demonstrated (Roche et al, 2008;Kerr et al, 2012;Duncan et al, 2013;Kerr et al, 2013b), there has been a paucity of studies examining if similar responses occur following activation of other TLRs. The synthetic cannabinoid WIN55,212-2 inhibits poly I:C-induced NF B activation and the expression of TNFα, while concurrently enhancing IRF3 signalling and IFNβ expression in a human astrocyte cell line .…”

Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators

“…injection of AM251, another CB1 receptor antagonist, at a dose that did not alter Tc in control rats per se (Fraga et al, 2009). Likewise, CB1 receptor-deficient mice do not develop fever to a LPS challenge (Duncan, et al, 2013) and peripheral administration of LPS increases AEA synthesis in the hypothalamus, and CB1, but not CB2 receptor protein expression (Fernandez-Solari et al, 2006, De Laurentiis et al, 2010. These data strongly point to a functional participation of the endocannabinoid system through a CB1 receptor in the fever induced by LPS.…”

“…Importantly, CB1 receptor deficient mice did not develop fever in response to LPS which seems to be related to the low expression of Toll-like 4 receptors (Duncan et al, 2013). Nakashima et al, (1995) suggested the involvement of an opioid receptor mechanism in the early but not in the late phase of the fever induced by IFN-α while our group showed the contribution of opioids through activation of µ-opioid receptors in the progress of fever induced by LPS and endogenous pyrogens TNF-α, IL-6, MIP-1α, CRH and ET-1 (Fraga et al, 2008).…”