No abstract

PD-L1 is up-regulated on neutrophils during sepsis, which may be related to sepsis-induced immunosuppression.

Background Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) is one of the critical inhibitory regulators of early stages of T cell activation and proliferation which opposes the actions of CD28-mediated co-stimulation. Anti-CTLA-4 therapy has been effective clinically in enhancing immunity and improving survival in patients with metastatic cancer. Sepsis is a lethal condition which shares many of the same mechanisms of immune suppression with cancer. Objectives Given the similarities in immune defects in cancer and sepsis, we examined the ability of anti-CTLA-4 antibody to block apoptosis, reverse the immunosuppression of sepsis, and improve survival in the cecal ligation and puncture (CLP) model. Measurements Mice underwent sham or CLP and spleens harvested at various time points after surgery. Expression of CTLA-4 on CD4, CD8, and regulatory T cells was quantitated. Anti-CTLA-4 was administrated 6 and 24hrs after surgery. Spleens were harvested at 48hrs post- surgery and apoptosis and cytokine production determined. Seven day survival studies were also conducted. Results Expression of CTLA-4 on CD4, CD8, and regulatory T cells increased during sepsis. Anti-CTLA-4 therapy decreased sepsis-induced apoptosis but had little effect on pro- or anti-inflammatory cytokines. There was a dose dependent effect of anti-CTLA-4 on survival. At high dose, anti-CTLA-4 worsened survival, but at lower doses, survival was significantly improved. Conclusion Survival in sepsis depends upon the proper balance between the pro- and anti-inflammatory/immunologic systems. Anti-CTLA-4 based immunotherapy offers promise in the treatment of sepsis but care must be used in the timing and dose of administration of the drug to prevent adverse effects.

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Background: Neuropathic pain is characterized by hyperalgesia, allodynia and spontaneous pain. It often occurs as a result of injury to peripheral nerves, dorsal root ganglions (DRG), spinal cord, or brain. Recent studies have suggested that Toll-like receptor 4 (TLR4) might play a role in neuropathic pain. Methodology/Principal Findings: In this study, we investigated the role of TLR4 in a rat chronic constriction injury (CCI) model and explored the feasibility of treating neuropathic pain by inhibiting TLR4. Our results demonstrated that intrathecal siRNA-mediated suppression of TLR4 attenuated CCI-induced mechanical allodynia and thermal hyperalgesia through inhibiting the activation of NF-κB p65 and production of proinflammatory cytokines (e.g., TNF-α and IL-1β). Conclusions/Significance: These findings suggest that suppression of TLR4 mediated by intrathecally administered siRNA may be a new strategy for the treatment of neuropathic pain.

Inflammatory diseases such as sepsis and autoimmune colitis, characterized by an overwhelming activation of the immune system and the counteracting anti-inflammatory response, remain a major health problem in worldwide. Emerging evidence suggests that methane have a protective effect on many animal models, like ischaemia reperfusion injury and diabetes-associated diseases. Whether methane could modulating inflammatory diseases remains largely unknown. Here we show that methane-rich saline (MS) ip treatment (16 ml/kg) alleviated endotoxin shock, bacteria-induced sepsis and dextran-sulfate-sodium-induced colitis in mice via decreased production of TNF-α and IL-6. In MS-treated macrophages, LPS-induced activation of NF-κb/MAPKs was attenuated. Interestingly, MS treatment significantly elevated the levels of IL-10 both in vitro and in vivo. Neutralization of IL-10 abrogated the therapeutic effect of MS. Moreover, anti-IL10 blockade partially restored the MS-mediated attenuation of NF-κb/MAPKs phosphorylation. We further found that MS resulted in markedly enhanced phosphorylation of GSK-3β and AKT, which both mediate the release of Il-10. Additionally, inhibition of PI3K attenuated MS-mediated p-GSK-3β and IL-10 production and reversed the suppressed activation of NF-κb/ MAPKs in response to LPS. Our results reveal a novel effect and mechanisms of methane and support the potential value of MS as a therapeutic approach in innate inflammatory diseases.

The coronavirus disease 2019, named COVID-19 officially by the World Health Organization (Geneva, Switzerland) on February 12, 2020, has spread at unprecedented speed. After the first outbreak in Wuhan, China, Chinese anesthesiologists encountered increasing numbers of infected patients since December 2019. Because the main route of transmission is via respiratory droplets and close contact, anesthesia providers are at a high risk when responding to the devastating mass emergency. So far, actions have been taken including but not limited to nationwide actions and online education regarding special procedures of airway management, oxygen therapy, ventilation support, hemodynamic management, sedation, and analgesia. As the epidemic situation has lasted for months (thus far), special platforms have also been set up to provide free mental health care to all anesthesia providers participating in acute and critical caring for COVID-19 patients. The current article documents the actions taken, lesson learned, and future work needed.

Acetate has been indicated to be elevated and to regulate inflammation in inflammatory and metabolic diseases. The inflammasome serves as a key component of immune homeostasis, and its dysregulation can lead to various inflammatory disorders. However, little is known about the effects of acetate on inflammasome activation and the underlying mechanism. Here, we demonstrate that acetate attenuates inflammasome activation via GPR43 in a Ca2+-dependent manner. Through binding to GPR43, acetate activates the Gq/11 subunit and subsequent phospholipase C-IP3 signaling to decrease Ca2+ mobilization. In addition, acetate activates soluble adenylyl cyclase (sAC), promotes NLRP3 inflammasome ubiquitination by PKA, and ultimately induces NLRP3 degradation through autophagy. In vivo, acetate protects mice from NLRP3 inflammasome-dependent peritonitis and LPS-induced endotoxemia. Collectively, our research demonstrates that acetate regulates the NLRP3 inflammasome via GPR43 and Ca2+-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasome attenuation and highlights acetate as a possible therapeutic strategy for NLRP3 inflammasome-related diseases.