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STING (Stimulator of interferon genes) is known as an important adaptor protein or direct sensor in the detection of nucleotide originating from pathogens or the host. The implication of STING during pulmonary microbial infection remains unknown to date. Herein, we showed that STING protected against pulmonary S.aureus infection by suppressing necroptosis. STING deficiency resulted in increased mortality, more bacteria burden in BALF and lungs, severe destruction of lung architecture, and elevated inflammatory cells infiltration and inflammatory cytokines secretion. STING deficiency also had a defect in bacterial clearance, but did not exacerbate pulmonary inflammation during the early stage of infection. Interestingly, TUNEL staining and LDH release assays showed that STING -/- mice had increased cell death than WT mice. We further demonstrated that STING -/- mice had decreased number of macrophages accompanied by increased dead macrophages. Our in vivo and in vitro findings further demonstrated this cell death as necroptosis. The critical role of necroptosis was detected by the fact that MLKL -/- mice exhibited decreased macrophage death and enhanced host defense to S.aureus infection. Importantly, blocking necroptosis activation rescued host defense defect against S.aureus pneumonia in STING -/- mice. Hence, these results reveal an important role of STING in suppressing necroptosis activation to facilitate early pathogen control during pulmonary S.aureus infection.

Background Drug-resistant bacteria have posed a great threat to animal breeding and human health. It is obviously urgent to develop new antibiotics that can effectively combat drug-resistant bacteria. The commensal flora inhabited in the intestines become potential candidates owing to the production of a wide range of antimicrobial substances. In addition, host genomes do not encode most of the enzymes needed to degrade dietary structural polysaccharides. The decomposition of these polysaccharides mainly depends on gut commensal-derived CAZymes. Results We report a novel species isolated from the chicken intestine, designated as Paenibacillus jilinensis sp. nov. and with YPG26 T (= CCTCC M2020899 T ) as the type strain. The complete genome of P. jilinensis YPG26 T is made up of a single circular chromosome measuring 3.97 Mb in length and containing 49.34% (mol%) G + C. It carries 33 rRNA genes, 89 tRNA genes, and 3871 protein-coding genes, among which abundant carbohydrate-degrading enzymes (CAZymes) are encoded. Moreover, this strain has the capability to antagonize multiple pathogens in vitro. We identified putative 6 BGCs encoding bacteriocin, NRPs, PKs, terpenes, and protcusin by genome mining. In addition, antibiotic susceptibility testing showed sensitivity to all antibiotics tested. Conclusions This study highlights the varieties of CAZymes genes and BGCs in the genome of Paenibacillus jilinensis . These findings confirm the beneficial function of the gut microbiota and also provide a promising candidate for the development of new carbohydrate degrading enzymes and antibacterial agents.

Gasdermin D (GSDMD), a member of the gasdermin protein family, is a caspase substrate, and its cleavage is required for pyroptosis and IL-1β secretion. To date, the role and regulatory mechanism of GSDMD during cutaneous microbial infection remain unclear. Here, we showed that GSDMD protected against Staphylococcus aureus skin infection by suppressing Cxcl1–Cxcr2 signalling. GSDMD deficiency resulted in larger abscesses, more bacterial colonization, exacerbated skin damage, and increased inflammatory cell infiltration. Although GSDMD deficiency resulted in defective IL-1β production, the critical role of IL-1β was counteracted by the fact that Caspase-1/11 deficiency also resulted in less IL-1β production but did not aggravate disease severity during S. aureus skin infection. Interestingly, GSDMD-deficient mice had increased Cxcl1 secretion accompanied by increased recruitment of neutrophils, whereas Caspase-1/11-deficient mice presented similar levels of Cxcl1 and neutrophils as wild-type mice. Moreover, the absence of GSDMD promoted Cxcl1 secretion in bone marrow-derived macrophages induced by live, dead, or different strains of S. aureus . Corresponding to higher transcription and secretion of Cxcl1, enhanced NF-κB activation was shown in vitro and in vivo in the absence of GSDMD. Importantly, inhibiting the Cxcl1–Cxcr2 axis with a Cxcr2 inhibitor or anti-Cxcl1 blocking antibody rescued host defence defects in the GSDMD-deficient mice. Hence, these results revealed an important role of GSDMD in suppressing the Cxcl1–Cxcr2 axis to facilitate pathogen control and prevent tissue damage during cutaneous S. aureus infection.

The intestinal mucosal barrier is critical for host defense against pathogens infection. Here, we demonstrate that the mixed lineage kinase-like protein (MLKL), a necroptosis effector, promotes intestinal epithelial barrier function by enhancing inflammasome activation. MLKL mice were more susceptible to infection compared with wild-type counterparts, with higher mortality rates, increased body weight loss, exacerbated intestinal inflammation, more bacterial colonization, and severe epithelial barrier disruption. MLKL deficiency promoted early epithelial colonization of prior to developing apparent intestinal pathology. Active MLKL was predominantly expressed in crypt epithelial cells, and experiments using bone marrow chimeras found that the protective effects of MLKL were dependent on its expression in non-hematopoietic cells. Intestinal mucosa of MLKL mice had impaired caspase-1 and gasdermin D cleavages and decreased interleukin (IL)-18 release. Moreover, administration of exogenous recombinant IL-18 rescued the phenotype of increased bacterial colonization in MLKL mice. Thus, our results uncover the role of MLKL in enhancing inflammasome activation in intestinal epithelial cells to inhibit early bacterial colonization.

Infectious agents can reach the placenta either the maternal blood or by ascending the genito-urinary tract, and then initially colonizing the maternal decidua. Decidual stromal cells (DSCs) are the major cellular component of the decidua. Although DSCs at the maternal-fetal interface contribute to the regulation of immunity in pregnancy in the face of immunological and physiological challenges, the roles of these DSCs during viral infection remain ill defined. Here, we characterized the response of DSCs to a synthetic double-stranded RNA molecule, polyinosinic-polycytidylic acid [poly(I:C)], which is a mimic of viral infection. We demonstrated that both transfection of cells with poly(I:C) and addition of extracellular (non-transfected) poly(I:C) trigger the necroptosis of DSCs and that this response is dependent on RIG-I-like receptor/IPS-1 signaling and the toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-β pathway, respectively. Furthermore, following poly(I:C) challenge, pregnant mixed lineage kinase domain-like protein-deficient mice had fewer necrotic cells in the mesometrial decidual layer, as well as milder pathological changes in the uterine unit, than did wild-type mice. Collectively, our results establish that necroptosis is a contributing factor in poly(I:C)-triggered abnormal pregnancy and thereby indicate a novel therapeutic strategy for reducing the severity of the adverse effects of viral infections in pregnancy.

The gut microbiota and microRNAs play important roles in the defense against infection. However, the role of miR-146a in L. monocytogenes infection and gut microbiota remains unclear. We tried to determine whether miR-146a controlled L. monocytogenes infection by regulating the gut microbiota. Wild-type and miR-146a-deficient mice or macrophages were used to characterize the impact of miR-146a on animal survival, cell death, bacterial clearance, and gut microbiota following L. monocytogenes challenge. We found that L. monocytogenes infection induced miR-146a expression both in vitro and in vivo. When compared to wild-type mice, miR-146a-deficient mice were more resistant to L. monocytogenes infection. MiR-146a deficiency in macrophages resulted in reduced invasion and intracellular survival of L. monocytogenes. High-throughput sequencing of 16S rRNA revealed that the gut microbiota composition differed between miR-146a-deficient and wild-type mice. Relative to wild-type mice, miR-146a-deficient mice had decreased levels of the Proteobacteria phylum, Prevotellaceae family, and Parasutterella genus, and significantly increased short-chain fatty acid producing bacteria, including the genera Alistipes, Blautia, Coprococcus_1, and Ruminococcus_1. Wild-type mice co-housed with miR-146a-deficient mice had increased resistance to L. monocytogenes, indicating that miR-146a deficiency guides the gut microbiota to alleviate infection. Together, these results suggest that miR-146a deficiency protects against L. monocytogenes infection by regulating the gut microbiota.

Due to its apparent rate-limiting function, BACE1 (β-secretase) appears to be a prime target for prevention of amyloid-β (Aβ) generation in brains with Alzheimer’s disease (AD). The activity of BACE1 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor binding site of the BACE1 promoter, indicating that PPARγ may be a potential target for AD treatment. Several studies have demonstrated that PPARγ activation is involved in the immunostimulation of amyloid-β precursor protein processing by nonsteroidal anti-inflammatory drugs (NSAIDs). The present study found that tripchlorolide (T 4 ), with a similar chemical structure to that of NSAIDs, decreased the levels of Aβ secreted in N2a-APP695 cells. T 4 treatment reduced the mRNA and protein levels of BACE1 and the protein level of sAPPβ, a cleaved N-terminal fragment of APP by BACE1. The treatment also translocated PPARγ from cytoplasm to nuclear. Intriguingly, T 4 , like pioglitazone (a PPARγ agonist), suppressed the BACE1 activity in N2a-APP695 cells, which was attenuated by GW9662 (a PPARγ antagonist). These results indicate that T 4 may be a PPARγ agonist to enhance the binding of nuclear PPARγ to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate the generation of Aβ. Due to its capability to alter Aβ generation and to protect central neural system against the neurotoxicity of Aβ, T 4 may serve as a promising agent in modulating Aβ-related pathology in Alzheimer’s disease.

Schwann cells play a critical role in peripheral nerve regeneration through dedifferentiation and proliferation. In a previous study, we performed microarray analysis of the sciatic nerve after injury. Accordingly, we predicted that long non-coding RNA NONMMUG014387 may promote Schwann cell proliferation after peripheral nerve injury, as bioinformatic analysis revealed that the target gene of NONMMUG014387 was collagen triple helix repeat containing 1（Cthrc1）. Cthrc1 may promote cell proliferation in a variety of cells by activating Wnt/PCP signaling. Nonetheless, bioinformatic analysis still needs to be verified by biological experiment. In this study, the candidate long non-coding RNA, NONMMUG014387, was overexpressed in mouse Schwann cells by recombinant adenovirus transfection. Plasmid p HBAd-MCMV-GFP-NONMMUG014387 and p HBAd-MCMV-GFP were transfected into Schwann cells. Schwann cells were divided into three groups： control（Schwann cells without intervention）, Ad-GFP（Schwann cells with GFP overexpression）, and Ad-NONMMUGO148387（Schwann cells with GFP and NONMMUGO148387 overexpression）. Cell Counting Kit-8 assay was used to evaluate proliferative capability of mouse Schwann cells after NONMMUG014387 overexpression. Polymerase chain reaction and western blot assay were performed to investigate target genes and downstream pathways of NONMMUG014387. Cell proliferation was significantly increased in Schwann cells overexpressing lnc RNA NONMMUG014387 compared with the other two groups. Further, compared with the control group, m RNA and protein levels of Cthrc1, Wnt5 a, ROR2, Rho A, Rac1, JNK, and ROCK were visibly up-regulated in the Ad-NONMMUGO148387 group. Our findings confirm that long non-coding RNA NONMMUG014387 can promote proliferation of Schwann cells surrounding the injury site through targeting Cthrc1 and activating the Wnt/PCP pathway.

Due to its apparent rate-limiting function, BACE1 ([beta]-secretase) appears to be a prime target for prevention of amyloid-[beta] (A[beta]) generation in brains with Alzheimer's disease (AD). The activity of BACE1 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor binding site of the BACE1 promoter, indicating that PPARγ may be a potential target for AD treatment. Several studies have demonstrated that PPARγ activation is involved in the immunostimulation of amyloid-[beta] precursor protein processing by nonsteroidal anti-inflammatory drugs (NSAIDs). The present study found that tripchlorolide (T4), with a similar chemical structure to that of NSAIDs, decreased the levels of A[beta] secreted in N2a-APP695 cells. T4 treatment reduced the mRNA and protein levels of BACE1 and the protein level of sAPP[beta], a cleaved N-terminal fragment of APP by BACE1. The treatment also translocated PPARγ from cytoplasm to nuclear. Intriguingly, T4, like pioglitazone (a PPARγ agonist), suppressed the BACE1 activity in N2a-APP695 cells, which was attenuated by GW9662 (a PPARγ antagonist). These results indicate that T4 may be a PPARγ agonist to enhance the binding of nuclear PPARγ to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate the generation of A[beta]. Due to its capability to alter A[beta] generation and to protect central neural system against the neurotoxicity of A[beta], T4 may serve as a promising agent in modulating A[beta]-related pathology in Alzheimer's disease.

Deferoxamine, a clinically safe drug used for treating iron overload, also repairs spinal cord injury although the mechanism for this action remains unknown. Here, we determined whether deferoxamine was therapeutic in a rat model of spinal cord injury and explored potential mechanisms for this effect. Spinal cord injury was induced by impacting the spinal cord at the thoracic T10 vertebra level. One group of injured rats received deferoxamine, a second injured group received saline, and a third group was sham operated. Both 2 days and 2 weeks after spinal cord injury, total iron ion levels and protein expression levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β and the pro-apoptotic protein caspase-3 in the spinal cords of the injured deferoxamine-treated rats were significantly lower than those in the injured saline-treated group. The percentage of the area positive for glial fibrillary acidic protein immunoreactivity and the number of terminal deoxynucleotidyl transferase d UTP nick end labeling-positive cells were also significantly decreased both 2 days and 2 weeks post injury, while the number of Neu N-positive cells and the percentage of the area positive for the oligodendrocyte marker CNPase were increased in the injured deferoxamine-treated rats. At 14–56 days post injury, hind limb motor function in the deferoxamine-treated rats was superior to that in the saline-treated rats. These results suggest that deferoxamine decreases total iron ion, tumor necrosis factor-α, interleukin-1β, and caspase-3 expression levels after spinal cord injury and inhibits apoptosis and glial scar formation to promote motor function recovery.