The complement receptor C5aR2 promotes protein kinase R expression and contributes to NLRP3 inflammasome activation and HMGB1 release from macrophages.

The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a multimeric protein complex that mediates maturation of the cytokines IL-1ß and IL-18 as well as release of the proinflammatory protein high-mobility group box 1 (HMGB1) and contributes to several inflammatory diseases, including sepsis, gout, and type 2 diabetes. In this context, the well-studied active complement fragment C5a and its receptor C5aR1 or C5aR2 orchestrate the inflammatory responses in many diseases. Although a C5a-C5aR interaction in NLRP3-associated diseases has been suggested, little is known about the details of C5a-C5aR cross-talk with the NLRP3 inflammasome in macrophages. In this study, using mice and murine macrophages and cytokines, immunoblotting, siRNA, and quantitative real-time PCR assays, we demonstrate that C5aR2 deficiency restricts activation of the NLRP3 inflammasome and release of HMGB1 both in vitro and in vivo Mechanistically, we found that C5aR2 promotes NLRP3 activation by amplifying dsRNA-dependent PKR expression, which is an important NLRP3-activating factor. We also observed that elevation of PKR expression because of the C5a-C5aR2 interaction depends on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase pathway and type I IFN signaling. In conclusion, these findings reveal that C5aR2 contributes to NLRP3 inflammasome activation and HMGB1 release from macrophages.

Caspse-11-GSDMD pathway is required for serum ferritin secretion in sepsis.

Ferritin is the major iron storage molecule of vertebrates, which can be detected in serum under numerous conditions, including inflammatory, neurodegenerative, and malignant diseases. Given this character, serum ferritin is frequently used as a biomarker in clinical settings. How the ferritin secreted to the serum has attracted much attention. Although some studies have found ferritin was mediated via the endoplasmic reticulum (ER)-Golgi secretion pathway or secretory lysosomes trafficking pathway under normal conditions, the secretion pathway of ferritin under pathological conditions, especially in sepsis is not very clear. In this report, we adopt a murine sepsis model to study the secretion pathway of ferritin in sepsis. We demonstrated caspase-11-GSDMD pathway and associated pyroptosis are required for secretion of ferritin in vitro and in vivo in sepsis. Moreover, our work connects pyroptosis to serum ferritin secretion and suggests a passive release process of ferritin, enhancing our understanding of the mechanism of ferritin secretion.

Clinical Effect Analysis of Laparoscopic Surgery for Gastric Tumor under Data Mining.

This paper mainly analyzes the feasibility of laparoscopic local gastrectomy for the treatment of benign gastric tumors, evaluating its curative effect, and the use of traditional Chinese medicine (TCM) such as Hedyotis diffusa, Radix Pseudostellariae, yi, Pinellia ternata, Ophiopogon japonicus, wood fragrance, Perilla, Scutellaria baicalensis, Yuzhu, hawthorn, Artemisia annua, chicken yellow film, nail, and turtle, and clinical symptoms of statistical analysis of data mining. A total of 86 patients with gastric benign tumor were selected as the research object and were divided into observation group and control group with 43 cases in each by the random number table method. The control group received radical gastrectomy for benign tumor under laparoscopy, while the observation group received local gastrectomy under laparoscopy. Perioperative indexes such as operative time, intraoperative blood loss, and length of hospital stay were recorded in the two groups. Serum C-reactive protein (CRP) and carcinoembryonic antigen (CEA) levels were analyzed by enzyme-linked immunosorbent assay (ELISA), and the incidence of complications was compared. Based on the clinical analysis of the drug used, the results of association significance were selected, and the top ten results were selected in order of confidence and grouped according to clinical symptoms, respectively, as follows: (1) abdominal distension: Hedyotis diffusa, Radix Pseudostellariae, Poria cocos, Huckleberry, and Coix seed; (2) dry mouth: Poria cocos, Radix Radix Pseudostellariae, Coix seed, Pinellia tuber, and Radix Ophiopogonis. The results showed that the minimum operation time in the observation group was 159.7 ± 13.07 min and the maximum was 172.57 ± 2.47 min, which was lower than that in the control group (the minimum was 172.46 ± 12.45 min and the maximum was 186.49 ± 24.32 min). The length of hospital stay (6.51 ± 1.29 days) was lower than that in the control group (7.56 ± 1.42 days) (P < 0.05). The CEA and CRP levels decreased significantly in both groups after treatment (P < 0.05). However, the observation group's CEA was (4.21 ± 1.05) mg/L and CRP was (8.46 ± 1.25) µg/L. In the control group, CEA was (4.18 ± 1.02) mg/L and CRP was (8.39 ± 1.24) µg/L. There were no significant differences (P < 0.05). The incidence of complications in the observed group was 4.7% lower than 7.0% in the control group (P < 0.05). Therefore, laparoscopic local gastric resection for benign gastric tumors can effectively reduce the incidence of CEA and CRP level and complications and improve the perioperative indicators, which is worth popularizing in clinical practice.

YAP promotes the activation of NLRP3 inflammasome via blocking K27-linked polyubiquitination of NLRP3.

The transcription coactivator YAP plays a vital role in Hippo pathway for organ-size control and tissue homeostasis. Recent studies have demonstrated YAP is closely related to immune disorders and inflammatory diseases, but the underlying mechanisms remain less defined. Here, we find that YAP promotes the activation of NLRP3 inflammasome, an intracellular multi-protein complex that orchestrates host immune responses to infections or sterile injuries. YAP deficiency in myeloid cells significantly attenuates LPS-induced systemic inflammation and monosodium urate (MSU) crystals-induced peritonitis. Mechanistically, YAP physically interacts with NLRP3 and maintains the stability of NLRP3 through blocking the association between NLRP3 and the E3 ligase ß-TrCP1, the latter increases the proteasomal degradation of NLRP3 via K27-linked ubiquitination at lys380. Together, these findings establish a role of YAP in the activation of NLRP3 inflammasome, and provide potential therapeutic target to treat the NLRP3 inflammasome-related diseases.

ß-catenin promotes NLRP3 inflammasome activation via increasing the association between NLRP3 and ASC.

NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome is involved in diverse inflammatory diseases, so the activation of NLRP3 inflammasome needs to be tightly regulated to prevent excessive inflammation. However, the endogenous regulatory mechanisms of NLRP3 inflammasome are still less defined. Here, we report that ß-catenin, which is the central mediator of the canonical Wnt/ß-catenin signaling, promotes NLRP3 inflammasome activation. When we suppressed the expression of ß-catenin by siRNA or pharmacological inhibitor, the NLRP3 inflammasome activation was impaired. Accordingly, ß-catenin inhibitor attenuated LPS-induced systemic inflammation in vivo. Mechanistically, we found ß-catenin interacted with NLRP3 and promoted the association between NLRP3 and ASC. Thus, our study revealed a novel role of ß-catenin in NLRP3 inflammasome activation and suggest an endogenous crosstalk between Wnt/ß-catenin signal and NLRP3 inflammasome.