Immunology letters最新文献

Background

Interleukin (IL)-41 is a recently discovered secreted protein that is expressed in a variety of tissues, and it is associated with several immune and metabolic diseases. However, IL-41 has not been studied in hyperuricemia (HUA).

Methods

Forty-four HUA patients and 44 healthy controls (HCs) were included in this study, and we collected theirgeneral and biochemical parameters, including white blood cell, neutrophil, lymphocyte, and platelet counts, mean platelet volume, platelet distribution width, serum creatinine, blood urea nitrogen, fasting blood glucose, total triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, total protein, albumin, alkaline phosphatase, gamma-glutamyltransferase, and hemoglobin concentration. The level of serum IL-41 was determined using an enzyme-linked immunosorbent assay. Multivariate logistic regression analysis was exploited to identify the independent risk factors associated with HUA, and the clinical diagnostic value of IL-41 was analyzed by applying the receiver operating characteristic (ROC) curve. We assessed the association between IL-41 and clinical parameters with Spearman's rank correlation.

Results

Circulating IL-41 levels were significantly higher in HUA patients than in the HCs group (460.3 pg/mL vs. 261.3 pg/mL, respectively; P < 0.001). The area under the ROC curve (AUC) for IL-41 in HUA patients was 0.7443 (with a cut-off value of 311.055 pg/mL, a sensitivity of 68.18 %, and a specificity of 72.73 %), while the AUC for IL-41 combined with the platelet count was 0.8109. Correlation analysis revealed that the circulating IL-41 level was positively correlated with age in HCs and HUA patients.

Conclusions

We herein demonstrated that serum IL-41 was elevated in HUA patients and that it may constitute a novel biomarker of anti-inflammatory response related to HUA.

Background

Intracerebral hemorrhage (ICH) is a serious medical problem, and promising strategy is limited. Macrophage initiated brain inflammatory injury following ICH, but the molecular mechanism had not been well identified. E3 ligase Nedd4L is implicated in the pathogenesis of the inflammatory immune response.

Methods

In the present study, we detected the levels of Nedd4L in macrophages following ICH. Furthermore, Macrophage M1 polarization, pro-inflammatory cytokine production, BBB disruption, brain water content and neurological function were examined in ICH mice.

Results

Here, we demonstrated that E3 ligase Nedd4L levels of macrophage increased following ICH, promoted M1 polarization inflammation by TRAF3. Nedd4L promoted BBB disruption, as well as neurological deficits. Inhibition of Nedd4L significantly attenuated M1 polarization in vivo. Inhibition of Nedd4L decreased TRAF3 and TBK1 levels, and subsequent phosphorylation of p38 and NF-κB p65 subunit following ICH.

Conclusions

Our data demonstrated that Nedd4L was involved in the pathogenesis of ICH, which promoted inflammatory responses and exacerbated brain damage by TRAF3 following ICH.

Background

It has been reported that cannabinoid receptors 2 (CB2 receptors) play an important role in the pathophysiological process of sepsis, which may also be associated with the regulation of pyroptosis, an inflammatory programmed cell death. The present study aimed to investigate the protective effect of CB2 receptors on myocardial damage in a model of septic mice by inhibiting pyroptosis.

Methods

The C57BL/6 mice underwent cecal ligation and puncture (CLP) to induce sepsis. All mice were randomly divided into the sham, CLP, or CLP+HU308 group. Blood and heart tissue samples were collected 12 h after surgery. Hematoxylin and eosin staining was used for analyzing histopathological results. Creatine kinase isoenzymes (CK-MB) and IL-1β were measured using ELISA, while lactate dehydrogenase (LDH) level was determined using photoelectric colorimetry. The expression levels of CB2 receptors and pyroptosis-associated proteins (NLRP3, caspase-1, and GSDMD) were measured using western blotting. The location and distribution of CB2 receptors and caspase-1 in myocardial tissues were assessed by immunofluorescence. TUNEL staining was used to quantify the number of dead cells in myocardial tissues.

Results

The CLP procedure increased CB2 receptor expression in mice. CB2 receptors were located in myocardial macrophages. Activating CB2 receptors decreased the levels of myocardial damage mediator LDH, CK-MB, and inflammatory cytokine IL-1β. The results also showed that CLP increased the pyroptosis in myocardial tissues, while CB2 agonist HU308 inhibited pyroptosis by decreasing the level of NLRP3 and activating caspase-1 and GSDMD.

Conclusions

CB2 receptor activation has a protective effect on the myocardium of mice with sepsis by inhibiting pyroptosis.

Transcriptional repressor, hypermethylated in cancer 1 (HIC1) participates in a range of important biological processes, such as tumor repression, immune suppression, embryonic development and epigenetic gene regulation. Further to these, we previously demonstrated that HIC1 provides a significant contribution to the function and development of regulatory T (Treg) cells. However, the mechanism by which it regulates these processes was not apparent. To address this question, we used affinity-purification mass spectrometry to characterize the HIC1 interactome in human Treg cells. Altogether 61 high-confidence interactors were identified, including IKZF3, which is a key transcription factor in the development of Treg cells. The biological processes associated with these interacting proteins include protein transport, mRNA processing, non-coding (ncRNA) transcription and RNA metabolism. The results revealed that HIC1 is part of a FOXP3-RUNX1-CBFB protein complex that regulates Treg signature genes thus improving our understanding of HIC1 function during early Treg cell differentiation.

The role of inflammation in pulmonary hypertension is gradually gaining increasing research attention. However, no previous study has evaluated the characteristics of inflammation during chronic hypoxia-induced pulmonary hypertension. Therefore, the aim of this study was to investigate the characteristics of the inflammatory process involved in hypoxia-induced pulmonary hypertension in mice. The current study evaluated from day 4 to day 28 of hypoxia, the PAAT and PAAT/PET decreased, accompanied by pulmonary vascular remodeling and right ventricular hypertrophy, as well as increased numbers of CD68 macrophages. The expression of the pro-inflammatory factors IL-1β and IL-33 increased, but decreased on day 28. The expression of IL-12 increased from day 4 to day 28, whereas that of the anti-inflammatory factor IL-10 in lung tissue decreased. Furthermore, the expression of the IL-33/ST2 signaling pathway also increased over time under hypoxic conditions. In conclusion, pulmonary artery remodeling in HPH mice worsens progressively in a time-dependent manner, with inflammatory cell infiltration predominating in the early stage and pulmonary vascular remodeling occurring in the later stage.

The significant number of deaths and infection caused by the new coronavirus SARS-CoV-2 has created an urgent demand for effective and readily available drugs for the treatment of COVID-19. However, the requirements for biosafety level 3 (NB-3) laboratories for experiments with the virus has made it very challenging for such research to meet this demand. It is known that angiotensin-converting enzyme 2 (ACE2), located on the surface of host cells, serves as the viral receptor for the spike (S) protein of SARS-CoV-2. This protein is a tetramer subdivided into S1 and S2 regions, with the former containing the receptor-binding domain (RBD). Therefore, drugs that interfere with the interaction between the spike and the receptor (as well as accessory proteins) or suppress their expression could inhibit the entry and spread of SARS-CoV-2 between cells. In this context, we standardized the use of recombinant SARS-CoV-2 S1 Protein with hFc (human Fc) for the analysis of binding in VERO E6 cells by flow cytometry, aiming to provide a new tool for identifying drugs and neutralizing antibodies, thus eliminating the need for NB-3 laboratories. Because minocycline (MCL), nimesulide (NMS), and berberine (BBR) have effects related to the ACE2 receptor, inhibit inflammation, and do not suppress the adaptive immune response (crucial for patient recovery), we investigated whether these drugs prevent the absorption of the spike protein into the host cell. For this purpose, we used VERO E6 cells under control conditions, pre-treated with these drugs and exposed to recombinant SARS-CoV-2 S1 Protein with hFC. We found that an exposure time of 30 min and a concentration of 10 μg/mL of spike S1 caused a strong signal detected by flow cytometry, using the secondary anti-hFc antibody conjugated with Alexa Fluor 647. Pre-treatment of cells with BBR for 30 min suppressed the signal from spike-positive cells, suggesting that this alkaloid interferes with spike adsorption on ACE2. The pre-incubation of spike protein with BBR did not alter its adsorption and internalization, indicating that BBR does not directly interact with spike protein. The ACE2 inactivation with a specific antibody inhibited spike protein adsorption and internalization. Furthermore, the pharmacological treatments did not alter the expression of ACE2. Exposure to spike protein increased IFNγ levels and the treatments with MCL and NMS were effective in inhibiting this increase. Taken together, we standardized a technique for analyzing the adsorption of SARS-CoV-2 and studying molecules that inhibit this process. Additionally, we demonstrated that BBR blocks spike entry bypre-binding to the host cell,and that the ACE2 receptor inactivation prevents Spike protein adsorption and penetration into cells.