SUMMARY The NF-κB pathway plays important roles in immune responses. Although its regulation has been extensively studied, here, we report an unknown feedforward mechanism for the regulation of this pathway by Toll-like receptor (TLR) ligands in macrophages. During bacterial infections, TLR ligands upregulate the expression of the 11S proteasome subunit PSME3 via NF-κB-mediated transcription in macrophages. PSME3, in turn, enhances the transcriptional activity of NF-κB by directly binding to and destabilizing KLF2, a negative regulator of NF-κB transcriptional activity. Consistent with this positive role of PSME3 in NF-κB regulation and importance of the NF-κB pathway in host defense against bacterial infections, the lack of PSME3 in hematopoietic cells renders the hosts more susceptible to bacterial infections, accompanied by increased bacterial burdens in host tissues. Thus, this study identifies a substrate for PSME3 and elucidates a proteolysis-dependent, but ubiquitin-independent, mechanism for NF-κB regulation that is important for host defense and innate immunity.

Background: The current meta-analytic study explored the relation between ACE gene insertion/deletion (I/D), and the risk of EH by reviewing relevant trials so as to determine the association between Angiotensin Converting Enzyme (ACE) gene polymorphism and essential hypertension (EH) susceptibility. Methods: Relevant studies published before May 2019 were collected from the PubMed, Cochrane, Embase, CNKI, VANFUN, and VIP databases. Results: Fifty-seven studies involving a total of 32,862 patients were included. These studies found that ACE gene D allele was associated with higher EH susceptibility in allelic model, homozygote model, dominant model, and regressive model, and that Asian population with ACE gene D allele showed a higher EH susceptibility in all these models. Moreover, ACE gene D allele was found closely related to a higher EH susceptibility in the subgroups of HWE, NO HWE, Caucasian population, and Mixed population, with the majority being males in allelic model, homozygote model, and regressive model and the majority being females in allelic model. Conclusion: ACE gene D allele is associated with an overall higher EH susceptibility, which is confirmed in the subgroup analysis of Asian population, HWE, NO HWE, Caucasian population, and Mixed population.

The gut microbiota plays a key role in regulating intracerebral hemorrhage (ICH)-induced neuroinflammation. The anti-neuroinflammatory effects of metformin (Met) have been reported in many central nervous system (CNS) diseases. However, whether Met regulates neuroinflammation through the gut microbiota in ICH-induced brain injury remains unknown. We found that Met treatment substantially alleviated neurological dysfunction and reduced neuroinflammation by inhibiting pro-inflammatory polarization of microglia/macrophages in mice with ICH. Moreover, Met treatment altered the microbiota composition and improved intestinal barrier function. The expression of lipopolysaccharide-binding protein (LBP), a biomarker of intestinal barrier damage, was also significantly reduced by Met treatment. Neuroinflammation was also potently ameliorated after the transplantation of fecal microbiota from Met-treated ICH mice. The neuroprotective effects of fecal microbiota transplantation (FMT) were similar to those of oral Met treatment. However, suppression of the gut microbiota negated the neuroprotective effects of Met in ICH mice. Therefore, Met is a promising therapeutic agent for neuroinflammation owing to ICH-induced imbalance of the gut microbiota.

AimPrevious studies have proved that inhibiting inflammasome activation provides neuroprotection against early brain injury (EBI) after subarachnoid hemorrhage (SAH), which is mainly focused on the microglial inflammatory response, but the potential role of neuronal inflammasome activation in EBI has not been clearly identified. This study examined whether the pannexin-1 channel inhibitor probenecid could reduce EBI after SAH by inhibiting neuronal AIM2 inflammasome activation.MethodsThere are in vivo and in vitro parts in this study. First, adult male SD rats were subjected to the endovascular perforation mode of SAH. The time course of pannexin-1 and AIM2 expressions were determined after SAH in 72 h. Brain water content, neurological function, AIM2 inflammasome activation, and inflammatory response were evaluated at 24 h after SAH in sham, SAH, and SAH + probenecid groups. In the in vitro part, HT22 cell treated with hemin was applied to mimic SAH. The expression of AIM2 inflammasome was detected by immunofluorescence staining. Neuronal death and mitochondrial dysfunction were determined by the LDH assay kit and JC-1 staining.ResultsThe pannexin-1 and AIM2 protein levels were upregulated after SAH. Pannexin-1 channel inhibitor probenecid attenuated brain edema and improved neurological dysfunction by reducing AIM2 inflammasome activation and reactive oxygen species (ROS) generation after SAH in rats. Treating HT22 cells with hemin for 12 h resulted in AIM2 and caspase-1 upregulation and increased mitochondrial dysfunction and neuronal cell death. Probenecid significantly attenuated the hemin-induced AIM2 inflammasome activation and neuronal death.ConclusionsAIM2 inflammasome is activated in neurons after SAH. Pharmacological inhibition of the pannexin-1 channel by probenecid attenuated SAH-induced AIM2 inflammasome activation and EBI in vivo and hemin-induced AIM2 inflammasome activation and neuronal death in vitro.

Highlights Interception of CD47-SIRPα signaling is an elusive yet intriguing goal for anti-tumor immunotherapy since unbiased CD47 blockade by its antibody cannot avoid erythrocyte destruction. We previously reported that isoQC, a Golgi-resident enzyme lacking in mature erythrocyte, disrupts the binding of CD47 to SIRPα by downregulating pGlu-CD47 and its interaction with SIRPα (Cell research 2019. 29:502–505). In this study, we explored the possibility of utilizing isoQC inhibition to address the challenge of CD47 antibody treatment induced anemia. We discovered a new lead compound of isoQC inhibitor, Luteolin, and revealed that posttranslational modification may work as an immunotherapeutic target by abolishing immune checkpoint signaling.