Innate Inflammatory Responses Research Articles

TRIM21 of Micropterus salmoides exerts antiviral roles against largemouth bass ulcer syndrome virus

Tripartite motif 21 (TRIM21), a member of the TRIM family, plays an important role in apoptosis, autophagy and ubiquitination in human, and has been proven to play antiviral roles in different organisms. In this study, the TRIM21 gene of Micropterus salmoides (MsTRIM21) was cloned, and it encoded 376 amino acids, which showed 89.3% similarity with Micropterus dolomieu and 38.3% with homo sapiens. Bioinformatics analysis revealed MsTRIM21 contained four domains: C4HC3-type RING-variant (RINGv), coiled coil, PRY and SPRY. The high expression level of MsTRIM21 could be detected in liver, stomach and muscle of healthy Micropterus salmoides, and it was significantly upregulated in head kidney, muscle, gill and brain and significantly down-regulated in the stomach of Micropterus salmoides infected with largemouth bass ulcer syndrome virus (LBUSV). The overexpression of MsTRIM21 could significantly inhibit the viral replication in vitro, evidenced by the reduction of CPE severity and the downregulation of the viral gene transcription. In addition, the overexpression of MsTRIM21 could significantly increase the expression level of interferon regulatory factor (IRF) 3, IRF7, myxovirus resistance 1 (Mx1), interferon stimulated gene 15 (ISG15), double-stranded RNA-activated protein kinase (PKR) and tumor necrosis factor α (TNF-α) in vitro, indicating the enhancement of innate immune response and inflammatory response, which may directly affect the replication of LBUSV. Thus, these results provide new lights on the roles of fish TRIM21 in innate immune response against iridovirus.

Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells

Cognate interaction between CD4+ effector memory T (TEM) cells and dendritic cells (DCs) induces innate inflammatory cytokine production, resulting in detrimental autoimmune pathology and cytokine storms. While TEM cells use tumor necrosis factor (TNF) superfamily ligands to activate DCs, whether TEM cells prompt other DC-intrinsic changes that influence the innate inflammatory response has never been investigated. We report the surprising discovery that TEM cells trigger double-strand DNA breaks via mitochondrial reactive oxygen species (ROS) production in interacting DCs. Initiation of the DNA damage response in DCs induces activation of a cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-independent, non-canonicalstimulator of interferon genes (STING)-TNF receptor-associated factor 6 (TRAF6)-nuclear factor κB (NF-κB) signaling axis. Consequently, STING-deficient DCs display reduced NF-κB activation and subsequent defects in transcriptional induction and functional production of interleukin-1β (IL-1β) and IL-6 following their interaction with TEM cells. The discovery of TEM cell-induced innate inflammation through DNA damage and a non-canonical STING-NF-κB pathway presents this pathway as a potential target to alleviate Tcell-driven inflammation in autoimmunity and cytokine storms.

The potential of microgreen as the dietary antioxidant in COVID-19 pandemic: mini review

Microgreens were tiny vegetables with a higher nutrient content than mature vegetables. Microgreens could be consumed directly as a garnish or salad. It was a high source of antioxidants and suitable for consumption. This review focused on providing a general description of microgreen production techniques, the nutritional content of microgreens, and their role in stimulating the immune system, mainly in preventing COVID-19. Several microgreens from various vegetables show high antioxidants, phytochemicals, and nutrients. This component is suitable for consumption to improve immunity system performance. The micronutrients contribute to immune function. There are four phases of the immune response in the body, namely physical barriers, innate immune response, inflammatory response, and adaptive immune response. When the body detects the presence of a foreign substance, the immune system will immediately respond by activating the immune function that utilizes T and B cells to kill them. Therefore, microgreen is one of the great dietary antioxidants for consumption.

Multiple sclerosis: Unveiling current immunogenetic factors and their role in etiopathogenesis and clinical aspects

Multiple sclerosis (MS) is the most common cause of neurological deficits among the young population. While the prevalence of MS is increasing worldwide, the incidence rate of MS is also undergoing a similar trend in Lithuania. Globally, women are twice as likely to be affected by MS as men. Unilateral optic neuritis is the most common initial symptom of MS. The signs and symptoms of MS vary greatly from patient to patient and depend on the location and severity of the nerve fiber damage in the central nervous system. Most people with MS have a relapsing-remitting disease course or clinically isolated syndrome. They experience periods of new symptoms or relapses that develop over days or weeks and usually resolve partially or completely. These relapses are followed by quiet periods of disease remission that may last months or even years. Data accumulated over the years suggest a complex interplay between environment and immunogenetics (strong associations with a large number of immune and genetic markers), and an increasingly convincing role of an underlying degenerative process leading to demyelination (in both white and gray matter), axonal and neurosynaptic damage, and a persistent innate inflammatory response, with T-cell-mediated autoimmunity appearing to play a diminishing role as the MS develops and progresses. In the absence of clinically proven, accurate, and reliable biomarkers, the disease can take a progressive course in case of late treatment, signifying the critical need for early diagnosis. This article therefore discusses the etiopathogenesis and clinical aspects of MS.

Graphene-Based Material-Mediated Immunomodulation in Tissue Engineering and Regeneration: Mechanism and Significance.

Tissue engineering and regenerative medicine hold promise for improving or even restoring the function of damaged organs. Graphene-based materials (GBMs) have become a key player in biomaterials applied to tissue engineering and regenerative medicine. A series of cellular and molecular events, which affect the outcome of tissue regeneration, occur after GBMs are implanted into the body. The immunomodulatory function of GBMs is considered to be a key factor influencing tissue regeneration. This review introduces the applications of GBMs in bone, neural, skin, and cardiovascular tissue engineering, emphasizing that the immunomodulatory functions of GBMs significantly improve tissue regeneration. This review focuses on summarizing and discussing the mechanisms by which GBMs mediate the sequential regulation of the innate immune cell inflammatory response. During the process of tissue healing, multiple immune responses, such as the inflammatory response, foreign body reaction, tissue fibrosis, and biodegradation of GBMs, are interrelated and influential. We discuss the regulation of these immune responses by GBMs, as well as the immune cells and related immunomodulatory mechanisms involved. Finally, we summarize the limitations in the immunomodulatory strategies of GBMs and ideas for optimizing GBM applications in tissue engineering. This review demonstrates the significance and related mechanism of the immunomodulatory function of GBM application in tissue engineering; more importantly, it contributes insights into the design of GBMs to enhance wound healing and tissue regeneration in tissue engineering.

An integrated multi-omics analysis of identifies distinct molecular characteristics in pulmonary infections of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.

Monitoring of Inflammasome Activation of Macrophages and Microglia In Vitro, Part 2: Assessing Inflammasome Activation.

Inflammasomes are macromolecular complexes that assemble upon the detection of cytoplasmic pathogen-associated or danger-associated signals and induce a necrotic type of cell death termed pyroptosis, facilitating pro-inflammatory cytokine release. Inflammasomes play a critical role in innate immunity and inflammatory response; however, they have also been associated with multiple diseases, including autoinflammatory and neurodegenerative conditions. In the following chapter, we describe methods to detect inflammasome activation and its downstream effects, including detection of ASC oligomerization, detection of activated caspase-1 and cleaved IL-1β, as well as read-outs for inflammasome-mediated cell death.

Immunology in COVID-19

So far, no effective vaccines or medicines have been licensed to prevent or treat the virus's rapid and global spread, urgent research is required to find preventative and therapeutic medicines. Treatments that target the immunopathology of SARS-CoV-2 infection have been a key focus in this respect. While a fast and well-coordinated immune response is the first line of defense against viral infection, an overly inflammatory innate response and a weakened adaptive host immunological response can cause tissue damage both at the site of virus entry and at the systemic level. Several investigations have identified significant alterations in the innate and adaptive immune systems in COVID-infected people. The enormous production of cytokines and chemokines, known as a "cytokine storm," plainly shows an uncontrolled dysregulation of the host immunological response. Although the idea of preventing cytokine storms is appealing, one important drawback is the lack of knowledge about the immunological signaling pathways triggered by SARS-CoV-2 infection. The discovery of altered signaling pathways during viral infections may aid in the deciphering of the most important molecular cascades involved in biological processes driving viral infections, as well as the identification of key molecular actors that might be targeted. Given the immune system's central involvement in COVID-19, a better understanding of the mechanism behind immunological dysregulation might lead to better therapeutic care of severe instances and the prevention of the disease's progression from moderate to severe. COVID-19 and supportive therapy remain the current standard of care. Keywords: COVID-19, SARS-CoV-2 infection, immunology, coronavirus illness 2019.

Plasmid-mediated virulence in Chlamydia.

Chlamydia trachomatis infection of ocular conjunctiva can lead to blindness, while infection of the female genital tract can lead to chronic pelvic pain, ectopic pregnancy, and/or infertility. Conjunctival and fallopian tube inflammation and the resulting disease sequelae are attributed to immune responses induced by chlamydial infection at these mucosal sites. The conserved chlamydial plasmid has been implicated in enhancing infection, via improved host cell entry and exit, and accelerating innate inflammatory responses that lead to tissue damage. The chlamydial plasmid encodes eight open reading frames, three of which have been associated with virulence: a secreted protein, Pgp3, and putative transcriptional regulators, Pgp4 and Pgp5. Although Pgp3 is an important plasmid-encoded virulence factor, recent studies suggest that chlamydial plasmid-mediated virulence extends beyond the expression of Pgp3. In this review, we discuss studies of genital, ocular, and gastrointestinal infection with C. trachomatis or C. muridarum that shed light on the role of the plasmid in disease development, and the potential for tissue and species-specific differences in plasmid-mediated pathogenesis. We also review evidence that plasmid-associated inflammation can be independent of bacterial burden. The functions of each of the plasmid-encoded proteins and potential molecular mechanisms for their role(s) in chlamydial virulence are discussed. Although the understanding of plasmid-associated virulence has expanded within the last decade, many questions related to how and to what extent the plasmid influences chlamydial infectivity and inflammation remain unknown, particularly with respect to human infections. Elucidating the answers to these questions could improve our understanding of how chlamydia augment infection and inflammation to cause disease.

Pro-inflammatory cytokines and reproductive hormone responses in bucks post-challenge with Mannheimia haemolytica A2 and its outer membrane protein.

The lipopolysaccharide (LPS) endotoxin and outer membrane protein (OMP) are among the virulence factors of Gram-negative bacteria responsible for inducing pathogenicity in the infected host. OMP and LPS occur on the outer membrane of M. haemolytica A2, the primary aetiological agent of pneumonic mannheimiosis in small ruminants. While the LPS is known to mediate Gram-negative bacterial infection by activating downstream inflammatory pathways, the potential role of OMP during inflammatory responses remained unclear. Hence, this study determined the effect of the OMP of M. haemolytica A2 on the serum concentration of pro-inflammatory cytokines and the male reproductive hormones (testosterone and Luteinizing Hormone). We randomly assigned twelve bucks to three groups (n = 4 bucks each): Group 1 was challenged with 2mL PBS buffer (pH 7.0) intranasally; Group 2 received 2mL of 1.2 X 109CFU/mL whole M. haemolytica A2 intranasally; and Group 3 received 2mL of OMP extract obtained from 1.2 X 109CFU/mL M. haemolytica A2 intramuscularly. Serum samples collected at pre-determined intervals were used for the quantitative determination of the pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) and reproductive hormones (testosterone and LH) using commercial sandwich enzyme-linked immunosorbent assay (ELISA). The serum concentration of IL1β was initially increased within the first-hour post-challenge in Groups 2 and 3, followed by a significant decrease in concentration at 21d and 35d (p < 0.05) in Group 3. Only mild fluctuations in IL-6 occurred in group 2, as opposed to the 1.7-fold rapid increase in TNFα within 2h post-challenge before decreasing at 6h. An increase in pro-inflammatory cytokines was accompanied by an acute febrile response of 39.5 ± 0.38°C (p < 0.05) at 2h and 40.1 ± 0.29°C (p < 0.05) at 4h in Group 2 and Group 3, respectively. Serum testosterone decreased significantly (p < 0.05) in both treatment groups but remained significantly (p > 0.05) lower than in Group 1 throughout the study. There was a moderate negative association between testosterone and IL1β (r = -0.473; p > 0.05) or TNFα (r = -0.527; p < 0.05) in Group 2. Serum LH also showed moderate negative associations with TNFα in Group 2 (r = -0.63; p < 0.05) and Group 3 (r = -0.54; p > 0.05). The results of this study demonstrated that M. haemolytica A2 and its OMP produced marked alterations in serum levels of pro-inflammatory cytokines and male reproductive hormones. The negative correlations between serum testosterone and inflammatory cytokines would suggest the potential role of OMP in causing male infertility by mediating innate inflammatory responses to suppress testosterone production in bucks.

Comparison of platelet-and endothelial-associated biomarkers of disease activity in people hospitalized with Covid-19 with and without HIV co-infection.

SARS-CoV-2 elicits a hyper-inflammatory response that contributes to increased morbidity and mortality in patients with COVID-19. In the case of HIV infection, despite effective anti-retroviral therapy, people living with HIV (PLWH) experience chronic systemic immune activation, which renders them particularly vulnerable to the life-threatening pulmonary, cardiovascular and other complications of SARS-CoV-2 co-infection. The focus of the study was a comparison of the concentrations of systemic indicators o\f innate immune dysfunction in SARS-CoV-2-PCR-positive patients (n=174) admitted with COVID-19, 37 of whom were co-infected with HIV. Participants were recruited from May 2020 to November 2021. Biomarkers included platelet-associated cytokines, chemokines, and growth factors (IL-1β, IL-6, IL-8, MIP-1α, RANTES, PDGF-BB, TGF-β1 and TNF-α) and endothelial associated markers (IL-1β, IL-1Ra, ICAM-1 and VEGF). PLWH were significantly younger (p=0.002) and more likely to be female (p=0.001); median CD4+ T-cell count was 256 (IQR 115 -388) cells/μL and the median HIV viral load (VL) was 20 (IQR 20 -12,980) copies/mL. Fractional inspired oxygen (FiO2) was high in both groups, but higher in patients without HIV infection (p=0.0165), reflecting a greater need for oxygen supplementation. With the exception of PDGF-BB, the levels of all the biomarkers of innate immune activation were increased in SARS-CoV-2/HIV-co-infected and SARS-CoV-2/HIV-uninfected sub-groups relative to those of a control group of healthy participants. The magnitudes of the increases in the levels of these biomarkers were comparable between the SARS-CoV-2 -infected sub-groups, the one exception being RANTES, which was significantly higher in the sub-group without HIV. After adjusting for age, sex, and diabetes in the multivariable model, only the association between HIV status and VEGF was statistically significant (p=0.034). VEGF was significantly higher in PLWH with a CD4+ T-cell count >200 cells/μL (p=0.040) and those with a suppressed VL (p=0.0077). These findings suggest that HIV co-infection is not associated with increased intensity of the systemic innate inflammatory response during SARS-CoV-2 co-infection, which may underpin the equivalent durations of hospital stay, outcome and mortality rates in the SARS-CoV-2/HIV-infected and -uninfected sub-groups investigated in the current study. The apparent association of increased levels of plasma VEGF with SARS-CoV-2/HIV co-infection does, however, merit further investigation.

Modulating the immune system as a therapeutic target for myelodysplastic syndromes and acute myeloid leukemia.

Modulating the immune system to treat diseases, including myeloid malignancies, has resulted in the development of a multitude of novel therapeutics in recent years. Myelodysplastic syndromes or neoplasms (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that arise from defects in hematopoietic stem and progenitor cells (HSPCs). Dysregulated immune responses, especially in innate immune and inflammatory pathways, are highly associated with the acquisition of HSPC defects in MDS and AML pathogenesis. In addition to utilizing the immune system in immunotherapeutic interventions such as chimeric antigen receptor T cell therapy, vaccines, and immune checkpoint inhibitors, mitigating dysregulation of innate immune and inflammatory responses in MDS and AML remains a priority in slowing the initiation and progression of these myeloid malignancies. This review provides a comprehensive summary of the current progress of diverse strategies to utilize or modulate the immune system in the treatment of MDS and AML.

A Review: The Potential Involvement of Growth Arrest-Specific 6 and Its Receptors in the Pathogenesis of Lung Damage and in Coronavirus Disease 2019.

The tyrosine kinase receptors of the TAM family-Tyro3, Axl and Mer-and their main ligand Gas6 (growth arrest-specific 6) have been implicated in several human diseases, having a particularly important role in the regulation of innate immunity and inflammatory response. The Gas6/TAM system is involved in the recognition of apoptotic debris by immune cells and this mechanism has been exploited by viruses for cell entry and infection. Coronavirus disease 2019 (COVID-19) is a multi-systemic disease, but the lungs are particularly affected during the acute phase and some patients may suffer persistent lung damage. Among the manifestations of the disease, fibrotic abnormalities have been observed among the survivors of COVID-19. The mechanisms of COVID-related fibrosis remain elusive, even though some parallels may be drawn with other fibrotic diseases, such as idiopathic pulmonary fibrosis. Due to the still limited number of scientific studies addressing this question, in this review we aimed to integrate the current knowledge of the Gas6/TAM axis with the pathophysiological mechanisms underlying COVID-19, with emphasis on the development of a fibrotic phenotype.

Infection of porcine enteroids and 2D differentiated intestinal epithelial cells with rotavirus A to study cell tropism and polarized immune response

ABSTRACT Intestinal epithelial cell interactions with enteric pathogens have been incompletely elucidated owing to the lack of model systems that recapitulate the cellular diversity, architecture and functionality of the intestine. To analyze rotavirus (RV) infection and the subsequent innate immune response, we established cultures of differentiated porcine intestinal epithelial cells in three different variations: basolateral-out enteroids, apical-out enteroids and two-dimensional (2D) filter-grown intestinal epithelial cells. Application of specific antibodies for fluorescent staining indicated that enteroids and enteroid-derived cell cultures contain multiple intestinal epithelial cell types. Infection studies indicated that both apical-out enteroids and 2D intestinal epithelial cells are susceptible to porcine RV infection. However, 2D intestinal epithelial cells are more useful for a detailed characterization and comparison of apical and basolateral infection than apical-out enteroids. Virus-induced apoptosis was observed in apical-out enteroids at 24 h post infection but not at earlier time points after infection. RV infected not only enterocytes but also goblet cells and Paneth cells in apical-out enteroids and 2D intestinal epithelial cells. Interestingly, despite the lack of significant differences in the efficiency of infection after apical and basolateral infection of 2D intestinal epithelial cells, stronger innate immune and inflammatory responses were observed after basolateral infection as compared to infection via the apical route. Therefore, apical-out enteroids and 2D intestinal epithelial cells provide useful primary cell culture models that can be extended to analyze invasion and replication strategies of agents implicated in enteric diseases or to study immune and inflammatory responses of the host induced by enteric pathogens.

Extracellular aaRSs drive autoimmune and inflammatory responses in rheumatoid arthritis via the release of cytokines and PAD4

ObjectivesRecent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to understand the role of extracellular aaRSs in the pathogenesis of...

Targeting Inflammasome Activation in Viral Infection: A Therapeutic Solution?

Inflammasome activation is exclusively involved in sensing activation of innate immunity and inflammatory response during viral infection. Accumulating evidence suggests that the manipulation of inflammasome assembly or its interaction with viral proteins are critical factors in viral pathogenesis. Results from pilot clinical trials show encouraging results of NLRP3 inflammasome suppression in reducing mortality and morbidity in SARS-CoV-2-infected patients. In this article, we summarize the up-to-date understanding of inflammasomes, including NLRP3, AIM2, NLRP1, NLRP6, and NLRC4 in various viral infections, with particular focus on RNA viruses such as SARS-CoV-2, HIV, IAV, and Zika virus and DNA viruses such as herpes simplex virus 1. We also discuss the current achievement of the mechanisms involved in viral infection-induced inflammatory response, host defense, and possible therapeutic solutions.

Whole tumour cell-based vaccines: tuning the instruments to orchestrate an optimal antitumour immune response.

Immunotherapy, particularly those based on immune checkpoint inhibitors (ICIs), has become a useful approach for many neoplastic diseases. Despite the improvements of ICIs in supporting tumour regression and prolonging survival, many patients do not respond or develop resistance to treatment. Thus, therapies that enhance antitumour immunity, such as anticancer vaccines, constitute a feasible and promising therapeutic strategy. Whole tumour cell (WTC) vaccines have been extensively tested in clinical studies as intact or genetically modified cells or tumour lysates, injected directly or loaded on DCs with distinct adjuvants. The essential requirements of WTC vaccines include the optimal delivery of a broad battery of tumour-associated antigens, the presence of tumour cell-derived molecular danger signals, and adequate adjuvants. These factors trigger an early and robust local innate inflammatory response that orchestrates an antigen-specific and proinflammatory adaptive antitumour response capable of controlling tumour growth by several mechanisms. In this review, the strengths and weaknesses of our own and others' experiences in studying WTC vaccines are revised to discuss the essential elements required to increase anticancer vaccine effectiveness.

Innate immune activation and white matter injury in a rat model of neonatal intraventricular hemorrhage are dependent on developmental stage

BackgroundInflammation and white matter injury are consequences of neonatal intraventricular hemorrhage (IVH). Both white matter and the neuroimmune system are developing during the time which IVH occurs and its consequences develop. IVH has been studied in many different animal models; however, the effects of IVH occurring at different developmental time points in the same model have not been examined. Understanding how the timing of IVH affects outcome may provide important insights into both IVH pathophysiology and innate immune development. MethodsWe used intraventricular injection of lysed whole blood to model neonatal IVH in postnatal day (P)2 and P5 rats. Flow cytometry was used to detect innate immune activation. MRI was used to screen animals for the development of increased ventricular size. Immunohistochemistry for myelin basic protein was used to quantify white matter and corpus callosum thickness. ResultsP5 animals exhibited significant increases in several measures of classically pro-inflammatory innate immune activation that P2 animals did not. Animals with IVH induced at P5 also developed ventricular enlargement visible on MRI whereas animals with IVH induced at P2 did not. On histological analysis, there were no significant effects of IVH in P2 animals, but IVH in P5 animals reduced white matter labeling and corpus callosum thickness. ConclusionsIVH induces a strong innate inflammatory response in P5 as well as changes in ventricular size and reduction of white matter. P2 animals do not exhibit significant changes in innate immune activation or white matter structure after IVH. This suggests that white matter pathology from IVH is due in part to innate immune activation; and that the developmental stage of the innate immune system is a key determinant of IVH pathology.

#5165 STING CONTRIBUTES TO LPS-INDUCED TUBULAR INFLAMMATION BY ACTIVATING IRE1/XBP1 PATHWAY IN ACUTE KIDNEY INJURY

Abstract Background and Aims Innate immunity and inflammation were recognized as the key factors for the progression of acute kidney injury (AKI) induced by lipopolysaccharide (LPS). Stimulator of interferon genes (STING) has emerged as a critical component of innate immune and inflammatory responses. This study aimed to explore the role of STING in LPS-induced tubular inflammation in AKI. Method 1. The AKI mice models were induced by intraperitoneal injection of LPS. Mice were randomly divided into CTL group, LPS 24 h group and LPS 48 h group: (1) STING protein expression in tubules was detected by IHC staining; (2) STING protein expression in kidney cortices was detected by WB. 2. The tubule-specific STING knockout (STING-cKO) mice were generated. Then WT mice and STING-cKO mice were randomly divided into WT group, WT+LPS group, STING-cKO group and STING-cKO+LPS group: (1) Blood samples and urine samples were collected for Scr, BUN and ACR measurement; (2) Tubular pathological changes were detected by PAS staining; (3) Inflammatory cell infiltration in kidney cortices was detected by IHC and IF staining; (4) Pro-inflammatory cytokines’ mRNA level in kidney cortices was detected by QPCR; (5) IRE1, XBP1, IL-1β and IL-18 protein expression in kidney cortices was detected by WB. 3. HK2 cells were randomly divided into CTL group, si-STING (STING siRNA) group, LPS group, LPS+si-STING group, Ad-IRE1 (IRE1 overexpression plasmid) group, si-STING+ Ad-IRE1 group, LPS+ Ad-IRE1 group and LPS+ si-STING+ Ad-IRE1 group: (1) Pro-inflammatory cytokines’ mRNA level was detected by QPCR; (2) IL-1β, IL-18 protein expression was detected by WB. Results 1. STING was activated in tubules from LPS-induced AKI mice. 2. STING-cKO significantly suppressed LPS-induced renal dysfunction, tubular pathological changes, tubular inflammation and IRE1/XBP1 pathway activation. 3.IRE1 overexpression significantly promoted LPS-activated HK2 cells’ inflammation, even though STING was silenced. Conclusion STING contributes to LPS-induced tubular inflammation by activating IRE1/XBP1 pathway. Targeting STING may be a promising therapeutic strategy for preventing septic AKI.

Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood-Brain Barrier and the Risk of Dementia.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.