A Review on the Immunomodulatory Mechanism of Acupuncture in the Treatment of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disease with a high prevalence and canceration rate. The immune disorder is one of the recognized mechanisms. Acupuncture is widely used to treat patients with IBD. In recent years, an increasing number of studies have proven the effectiveness of acupuncture in the treatment of IBD, and some progress has been made in the mechanism. In this paper, we reviewed the studies related to acupuncture for IBD and focused on the immunomodulatory mechanism. We found that acupuncture could regulate the innate and adaptive immunity of IBD patients in many ways. Acupuncture exerts innate immunomodulatory effects by regulating intestinal epithelial barrier, toll-like receptors, NLRP3 inflammasomes, oxidative stress, and endoplasmic reticulum stress and exerts adaptive immunomodulation by regulating the balance of Th17/Treg and Th1/Th2 cells. In addition, acupuncture can also regulate intestinal flora.

Cellular Deubiquitylating Enzyme: A Regulatory Factor of Antiviral Innate Immunity

Deubiquitylating enzymes (DUBs) are proteases that crack the ubiquitin code from ubiquitylated substrates to reverse the fate of substrate proteins. Recently, DUBs have been found to mediate various cellular biological functions, including antiviral innate immune response mediated by pattern-recognition receptors (PRRs) and NLR Family pyrin domain containing 3 (NLRP3) inflammasomes. So far, many DUBs have been identified to exert a distinct function in fine-tuning antiviral innate immunity and are utilized by viruses for immune evasion. Here, the recent advances in the regulation of antiviral responses by DUBs are reviewed. We also discussed the DUBs-mediated interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and antiviral innate immunity. The understanding of the mechanisms on antiviral innate immunity regulated by DUBs may provide therapeutic opportunities for viral infection.

Potential role of BAY11-7082, a NF-κB blocker inhibiting experimental autoimmune encephalomyelitis in C57BL/6J mice via declining NLRP3 inflammasomes

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease of the central nervous system. NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, is implicated in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the exact mechanism by which NLRP3 inflammasome is involved in the development of MS and EAE is not clear. NF-kappaB (NF-κB) is associated with the activity of NLRP3 inflammasomes, but the role of NF-κB is controversial. We sought to demonstrate that both NF-κB and NLRP3 contribute to development of MS and EAE, and NF-κB pathway is positively correlated with NLRP3 activation in EAE. The inhibitor of NF-κB and NLRP3, BAY11-7082, can prevent and treat EAE. BAY11-7082 (5mg/kg/i.p and 20 mg/kg/i.p) was intraperitoneally administered to EAE mice at the time of second injection of pertussis toxin (BAY11-7082 prevention group) or at the onset of symptoms (BAY11-7082 treatment group). mRNA expressions of NLRP3 were determined by qPCR. Protein expressions of NLRP3, NF-κBp65, and phosphorylated-p65 were determined by Western blotting. Serum levels of inflammatory cytokines were measured by Cytometric Bead Array. Mice treated with BAY11-7082 (both prevention and treatment groups) showed lower clinical scores and attenuated pathological changes. NLRP3 inflammasome and activity of NF-κB in spinal cord of EAE mice was higher than that in control group. However, the level of NLRP3 inflammasome decreased in BAY11-7082 prevention and treatment groups. BAY11-7082 is a promising therapeutic agent for MS. NLRP3 activation in EAE maybe related with NF-κB pathway.

Leptin Induces Apoptotic and Pyroptotic Cell Death via NLRP3 Inflammasome Activation in Rat Hepatocytes

Leptin, a hormone that is predominantly produced by adipose tissue, is closely associated with various liver diseases. However, there is a lack of understanding as to whether leptin directly induces cytotoxic effects in hepatocytes as well as the mechanisms that are involved. Inflammasomes, which are critical components in the innate immune system, have been recently shown to modulate cell death. In this study, we examined the effect of leptin on the viability of rat hepatocytes and the underlying mechanisms, with a particular focus on the role of inflammasomes activation. Leptin treatment induced cytotoxicity in rat hepatocytes, as determined by decreased cell viability, increased caspase-3 activity, and the enhanced release of lactate dehydrogenase. NLRP3 inflammasomes were activated by leptin both in vitro and in vivo, as determined by the maturation of interleukin-1β and caspase-1, and the increased expression of inflammasome components, including NLRP3 and ASC. Mechanistically, leptin-induced inflammasome activation is mediated via the axis of ROS production, ER stress, and autophagy. Notably, the inhibition of inflammasomes by treatment with the NLRP3 inhibitor or the IL-1 receptor antagonist protected the hepatocytes from leptin-induced cell death. Together, these results indicate that leptin exerts cytotoxic effects in hepatocytes, at least in part, via the activation of NLRP3 inflammasomes.

Knockdown of SNW1 ameliorates brain microvascular endothelial cells injury by inhibiting NLRP3 inflammasome activation

IntroductionSNW domain containing 1 (SNW1), as a splicing factor to regulate the activity of transcription factors, has been reported to be involved in multiple disease processes, including neuroblastoma. Whereas, the latent function and concrete mechanism of SNW1 in brain microvascular endothelial cells (BMECs) have not been clarified.Material and methodsBMECs were induced by oxidized low-density lipoprotein (ox-LDL), and high fat (HF)-fed rats were established. After SNW1 knockdown or NLR family pyrin domain containing 3 (NLRP3) overexpression, SNW1 and NLRP3 expressions were monitored via RT-qPCR, Western blot, or immunohistochemistry assays. Also, cell viability, apoptosis, and cholesterol efflux were determined via CCK-8, flow cytometry, and related kits; IL-18 and IL-3 levels were also certified by ELISA kits; and NLRP3 inflammasomes and cholesterol efflux-related proteins were identified by Western blot in vitro and in vivo.ResultsWe discovered that ox-LDL or HF-feeding significantly elevated SNW1 and NLRP3 expressions, and prominently induced BMECs injury in BMECs or rat brain tissues. Subsequently, our data confirmed that SNW1 knockdown markedly accelerated cholesterol efflux and viability, and prevented apoptosis and NLRP3 inflammasomes, which also could be reversed by NLRP3 overexpression in ox-LDL-induced BMECs. In addition, we showed that SNW1 knockdown could signally induce cholesterol efflux and repress NLRP3 inflammasome activation in HF-fed rats.ConclusionsWe demonstrated that SNW1 knockdown has a great protection effect on the dysfunction of BMECs by inhibiting NLRP3. So, SNW1 might be a therapeutic target for BMECs injury.

The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.