Stk24 protects against obesity-associated metabolic disorders by disrupting the NLRP3 inflammasome.

Adipose tissue macrophages (ATMs) regulate the occurrence of obesity and its related diseases. Here, we found that serine/threonine protein kinase 24 (Stk24) expression is downregulated significantly in ATMs in obese subjects or obese subjects with type 2 diabetes and mice fed a high-fat diet (HFD). We further identified that glucolipotoxicity downregulated Stk24 expression in ATMs. Stk24-deficient mice develop severe HFD-induced metabolic disorders and insulin insensitivity. Mechanistically, Stk24 intervenes in NLRP3 inflammasome assembly in ATMs by associating directly with NLRP3, decreasing interleukin-1ß (IL-1ß) secretion. Accordingly, Stk24 deficiency in the hematopoietic system promotes NLRP3 inflammasome activation, which contributes to exacerbation of metabolic disorders. Intriguingly, Stk24 expression correlates negatively with body mass index (BMI) and the levels of glucose, cholesterol, triglycerides, and low-density lipoprotein in human subjects. These findings provide insights into the function and clinical implications of Stk24 in obesity-mediated metabolic disorders.

The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases.

Aberrant inflammasome activation contributes to the pathogenesis of various human diseases, including atherosclerosis, gout, and metabolic disorders. Elucidation of the underlying mechanism involved in the negative regulation of the inflammasome is important for developing new therapeutic targets for these diseases. Here, we showed that Raf kinase inhibitor protein (RKIP) negatively regulates the activation of the NLRP1, NLRP3, and NLRC4 inflammasomes. RKIP deficiency enhanced caspase-1 activation and IL-1ß secretion via NLRP1, NLRP3, and NLRC4 inflammasome activation in primary macrophages. The overexpression of RKIP in THP-1 cells inhibited NLRP1, NLRP3, and NLRC4 inflammasome activation. RKIP-deficient mice showed increased sensitivity to Alum-induced peritonitis and Salmonella typhimurium-induced inflammation, indicating that RKIP inhibits NLRP3 and NLRC4 inflammasome activation in vivo. Mechanistically, RKIP directly binds to apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and competes with NLRP1, NLRP3, or NLRC4 to interact with ASC, thus interrupting inflammasome assembly and activation. The depletion of RKIP aggravated inflammasome-related diseases such as monosodium urate (MSU)-induced gouty arthritis and high-fat diet (HFD)-induced metabolic disorders. Furthermore, the expression of RKIP was substantially downregulated in patients with gouty arthritis or type 2 diabetes (T2D) compared to healthy controls. Collectively, our findings suggest that RKIP negatively regulates NLRP1, NLRP3, and NLRC4 inflammasome activation and is a potential therapeutic target for the treatment of inflammasome-related diseases.

Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop.

Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; however, IFNs also induce negative regulators that attenuate the antiviral response. Here, we show that both viral and bacterial invasion downregulate Nuclear Dbf2-related kinase 1 (NDR1) expression via the type I IFN signaling pathway. NDR1 promotes the virus-induced production of type I IFN, proinflammatory cytokines and ISGs in a kinase-independent manner. NDR1 deficiency also renders mice more susceptible to viral and bacterial infections. Mechanistically, NDR1 enhances STAT1 translation by directly binding to the intergenic region of miR146a, thereby inhibiting miR146a expression and liberating STAT1 from miR146a-mediated translational inhibition. Furthermore, STAT1 binds to the miR146a promoter, thus decreasing its expression. Together, our results suggest that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response, and suggest that NDR1 has an important role in controlling viral infections.

RKIP mediates autoimmune inflammation by positively regulating IL-17R signaling.

Th17 cells contribute to the development of autoimmune diseases by secreting interleukin-17 (IL-17), which activates its receptor (IL-17R) that is expressed on epithelial cells, macrophages, microglia, and resident neuroectodermal cells. However, the mechanisms through which IL-17R-mediated signaling contributes to the development of autoimmune disease have not been completely elucidated. Here, we demonstrate that Raf-1 kinase inhibitor protein (RKIP) deficiency in mice ameliorates the symptoms of experimental autoimmune encephalomyelitis (EAE). Adoptive T-cell-transfer experiments demonstrate that RKIP plays a predominant role in Th17-mediated, but not in Th1-mediated immune responses. RKIP deficiency has no effect on Th17-cell differentiation ex vivo, nor does it affect Th17-cell differentiation in EAE mice. However, RKIP significantly promotes IL-17R-induced proinflammatory cytokine and chemokine production. Mechanistically, RKIP directly interacts with IL-17RA and Act1 to promote the formation of an IL-17R-Act1 complex, resulting in enhanced MAPK- and P65-mediated NF-κB activation and downstream cytokine production. Together, these findings indicate that RKIP functions as an essential modulator of the IL-17R-Act1 axis in IL-17R signaling, which promotes IL-17-induced inflammation and autoimmune neuroinflammation.

Valorization of bamboo by γ-valerolactone/acid/water to produce digestible cellulose, degraded sugars and lignin.

A novel pretreatment process was developed to achieve valorization of bamboo components into digestible cellulose, degraded sugars and lignin. In this case, bamboo was pretreated with 60% γ-valerolactone (GVL)/40% water containing 0.05mol/L H2SO4, yielding solid fraction rich in cellulose. The resulting liquor was further treated with the addition of NaCl and ultrasound, resulting in water phase rich in degraded sugars and GVL phase containing lignin, which was easy to recover. Results showed that the enzymatic hydrolysis was enhanced by 6.7-fold after treatment as compared to the control. The degraded sugars released in water phase contained monosaccharides (70.72-160.47g/kg) together with oligo- and polysaccharides (46.4-181.85g/kg). The lignin obtained had high purity, low molecular weight (1820-2970gmol-1) and low polydispersity (1.93-1.98). The present study creates a novel pretreatment process for the conversion of Gramineae biomass into useful feedstocks with potential applications in the fields of fuels, chemicals and polymers.