TLR4 Receptor Induces 2-AG–Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells

International audienceMast cells (MCs) contribute to the control of local inflammatory reactions and become hyporesponsive after prolonged TLR4 activation by bacterial LPS. The molecular mechanisms involved in endotoxin tolerance (ET) induction in MCs are not fully understood. In this study, we demonstrate that the endocannabinoid 2-arachidonoylglycerol (2-AG) and its receptor, cannabinoid receptor 2 (CB2), play a role in the establishment of ET in bone marrow-derived MCs from C57BL/6J mice. We found that CB2 antagonism prevented the development of ET and that bone marrow-derived MCs produce 2-AG in a TLR4-dependent fashion. Exogenous 2-AG induced ET similarly to LPS, blocking the phosphorylation of IKK and the p65 subunit of NF-κB and inducing the synthesis of molecular markers of ET. LPS caused CB2 receptor trafficking in Rab11-, Rab7-, and Lamp2-positive vesicles, indicating recycling and degradation of the receptor. 2-AG also prevented LPS-induced TNF secretion in vivo, in a MC-dependent model of endotoxemia, demonstrating that TLR4 engagement leads to 2-AG secretion, which contributes to the negative control of MCs activation. Our study uncovers a functional role for the endocannabinoid system in the inhibition of MC-dependent innate immune responses in vivo

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

Obesity remains a global health problem. Chronic low-grade inflammation in this pathology has been related to comorbidities such as cognitive alterations that, in the long term, can lead to neurodegenerative diseases. Neuroinflammation or gliosis in patients with obesity and type 2 diabetes mellitus has been related to the effect of adipokines, high lipid levels and glucose, which increase the production of free radicals. Cerebral gliosis can be a risk factor for developing neurodegenerative diseases, and antioxidants could be an alternative for the prevention and treatment of neural comorbidities in obese patients. Aim: Identify the immunological and oxidative stress mechanisms that produce gliosis in patients with obesity and propose antioxidants as an alternative to reducing neuroinflammation. Method: Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index for research on the physiopathology of gliosis in obese patients and for the possible role of antioxidants in its management. Conclusion: Patients with obesity can develop neuroinflammation, conditioned by various adipokines, excess lipids and glucose, which results in an increase in free radicals that must be neutralized with antioxidants to reduce gliosis and the risk of long-term neurodegeneration

Participation of 5-HT(1B) receptors in the inhibitory actions of serotonin on masculine sexual behaviour of mice: pharmacological analysis in 5-HT(1B) receptor knockout mice

1. The role of the 5-Hydroxytryptamine(1B) (5-HT(1B)) receptor subtype in masculine sexual behaviour in mice was analysed in both 5-HT(1B) receptor knockout (KO(1B)) and wild-type (WT) animals. 2. Comparison of male copulatory behaviour of WT and KO(1B) strains revealed that KO(1B) mice become interested earlier in sexual behaviour, but require more stimulation to achieve ejaculation than its corresponding WT strain. 3. The pharmacological manipulation of male sexual activity in the WT strain showed that the serotonin precursor 5-Hydroxytryptophan (5-HTP), the 5-HT(1B) agonist (1-(m-trifluoromethylphenyl) piperazine (TFMPP) and the 5-Hydroxytryptamine(1A) (5-HT(1A)) receptor agonist 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT) all inhibited male copulatory behaviour in mice. 4. In KO(1B) mice, TFMPP lacked an effect, 5-HTP exerted a mild inhibitory effect while 8-OH-DPAT provoked only a tendency towards a reduction in the percentage of animals that achieved ejaculation. In general, KO(1B) mice were less sensitive to the inhibitory actions of 5-HTP and 8-OH-DPAT than the WT strain. 5. Based on these results, we can suggest that serotonin plays a general inhibitory role in the sexual behaviour of male mice and that both 5-HT(1B) and 5-HT(1A) receptor subtypes participate in the inhibitory actions of this neurotransmitter. 6. The absence of the 5-HT(1B) receptor subtype affected both components of mouse masculine sexual behaviour, motivation and execution, further confirming the involvement of this receptor subtype in the control of this behaviour. In addition, the diminished sensitivity to serotonergic stimulation exhibited by KO(1B) mice suggests the occurrence of compensatory changes as a consequence of the absence of the 5-HT(1B) receptor subtype