Innate Immunity最新文献

Increasing evidence indicates that signal transducer and activator of transcription 3 (STAT3), a vital transcription factor, plays crucial roles in the regulation of inflammation. STAT3 has become a novel therapeutic target for intervention in inflammation-related disorders. However, it remains unclear whether STAT3 plays a part in acute hepatic damage. To investigate the effects of STAT3 here, LPS/d-GalN-induced hepatic damage was induced in mice, the STAT3 inhibitor Stattic was administered, and the degree of liver injury, inflammation, and hepatocyte apoptosis were investigated. The results showed that Stattic mitigated the hepatic morphologic abnormalities and decreased the level of aminotransferase in LPS/D-GalN-insulted mice. The results also indicated that Stattic decreased the levels of TNF-α and IL-6, prevented the activation of the caspase cascade, suppressed cleavage of PARP, and decreased the quantity of TUNEL-positive cells. These results suggest that Stattic provided protective benefits in LPS/d-GalN-induced hepatic damage, and the protective effects might be associated with its anti-inflammatory and anti-apoptotic effects. Therefore, STAT3 might become a novel target for intervening in inflammation-based and apoptosis-based hepatic disorders.

Pseudomonas aeruginosa is an opportunistic bacterial pathogen of plants. Unlike the well-characterized plant defense responses to highly adapted bacterial phytopathogens, little is known about plant response to P. aeruginosa infection. In this study, we examined the Brassica napus (canola) tissue-specific response to P. aeruginosa infection using RNA sequencing. Transcriptomic analysis of canola seedlings over a 5 day P. aeruginosa infection revealed that many molecular processes involved in plant innate immunity were up-regulated, whereas photosynthesis was down-regulated. Phytohormones control many vital biological processes within plants, including growth and development, senescence, seed setting, fruit ripening, and innate immunity. The three main phytohormones involved in plant innate immunity are salicylic acid (SA), jasmonic acid (JA), and ethylene (ET). Many bacterial pathogens have evolved multiple strategies to manipulate these hormone responses in order to infect plants successfully. Interestingly, gene expression within all three phytohormone (SA, JA, and ET) signaling pathways was up-regulated in response to P. aeruginosa infection. This study identified a unique plant hormone response to the opportunistic bacterial pathogen P. aeruginosa infection.

Long non-coding RNAs (lncRNAs) are emerging as key regulators in inflammation. However, their functions and profiles in LPS-induced inflammation in pigs are largely unknown. In this study, we profiled global lncRNA and mRNA expression changes in PBMCs treated with LPS using the lncRNA-seq technique. In total 43 differentially expressed (DE) lncRNAs and 1082 DE mRNAs were identified in porcine PBMCs after LPS stimulation. Functional enrichment analysis on DE mRNAs indicated these genes were involved in inflammation-related signaling pathways, including cytokine-cytokine receptor interaction, TNF-α, NF-κB, Jak-STAT and TLR signaling pathways. In addition, co-expression network and function analysis identified the potential lncRNAs related to inflammatory response and immune response. The expressions of eight lncRNAs (ENSSSCT00000045208, ENSSSCT00000051636, ENSSSCT00000049770, ENSSSCT00000050966, ENSSSCT00000047491, ENSSSCT00000049750, ENSSSCT00000054262 and ENSSSCT00000044651) were validated in the LPS-treated PBMCs by quantitative real-time PCR (qRT-PCR). In LPS-challenged piglets, we identified that expression of three lncRNAs (ENSSSCT00000051636, ENSSSCT00000049770, and ENSSSCT00000047491) was significantly up-regulated in liver, spleen and jejunum tissues after LPS challenge, which indicated that these lncRNAs might be important regulators for inflammation. This study provides the first lncRNA and mRNA transcriptomic landscape of LPS-mediated changes in porcine PBMCs, which might provide potential insights into lncRNAs involved in regulating inflammation in pigs.

Recent data argue for a pro-inflammatory role of CAMP (cathelicidin antimicrobial peptide) in adipocytes and adipose tissue (AT) and for regulatory circuits involving TLRs. In order to investigate regulatory effects of TLR2 and TLR4, 3T3-L1 adipocytes were stimulated with TLR2 agonistic lipopeptide MALP-2 and with TLR4 agonist LPS in presence or absence of signal transduction inhibitors. CAMP gene expression was analysed by quantitative real-time PCR in adipocytes and in murine AT compartments and cellular subfractions. CAMP expression was higher in gonadal than in subcutaneous AT and there was a gender-specific effect with higher levels in males. Adipocytes had higher CAMP expression than the stroma-vascular cell (SVC) fraction. MALP-2 up-regulated CAMP expression significantly, mediated by STAT3 and PI3K and potentially (non-significant trend) by NF-κB and MAPK, but not by raf-activated MEK-1/-2. Moreover, LPS proved to act as a potent inducer of CAMP via NF-κB, PI3K and STAT3, whereas specific inhibition of MAPK and MEK-1/-2 had no effect. In conclusion, activation of TLR2 and TLR4 by classical ligands up-regulates adipocyte CAMP expression involving classical signal transduction elements. These might represent future drug targets for pharmacological modulation of CAMP expression in adipocytes, especially in the context of metabolic and infectious diseases.

The blood-brain barrier (BBB), which protects the CNS from pathogens, is composed of specialized brain microvascular endothelial cells (BMECs) joined by tight junctions and ensheathed by pericytes and astrocyte endfeet. The stability of the BBB structure and function is of great significance for the maintenance of brain homeostasis. When a neurotropic virus invades the CNS via a hematogenous or non-hematogenous route, it may cause structural and functional disorders of the BBB, and also activate the BBB anti-inflammatory or pro-inflammatory innate immune response. This article focuses on the structural and functional changes that occur in the three main components of the BBB (endothelial cells, astrocytes, and pericytes) in response to infection with neurotropic viruses transmitted by hematogenous routes, and also briefly describes the supportive effect of three cells on the BBB under normal physiological conditions. For example, all three types of cells express several PRRs, which can quickly sense the virus and make corresponding immune responses. The pro-inflammatory immune response will exacerbate the destruction of the BBB, while the anti-inflammatory immune response, based on type I IFN, consolidates the stability of the BBB. Exploring the details of the interaction between the host and the pathogen at the BBB during neurotropic virus infection will help to propose new treatments for viral encephalitis. Enhancing the defense function of the BBB, maintaining the integrity of the BBB, and suppressing the pro-inflammatory immune response of the BBB provide more ideas for limiting the neuroinvasion of neurotropic viruses. In the future, these new treatments are expected to cooperate with traditional antiviral methods to improve the therapeutic effect of viral encephalitis.

Brucella is a genus of Gram-negative intracellular pathogens that cause animal and human diseases. Brucella survival and replication inside immune cells is critical for the establishment of chronic infections. Protein modifications by small ubiquitin-related modifier proteins and the NF-κB pathway are involved in many cellular activities, playing major roles in regulating protein function that is essential for pathogenic bacteria during infection. However, the relationship between them in the intracellular survival of Brucella is still largely unknown. We demonstrated that Brucella abortus 2308 infection can activate the expression of small ubiquitin-related modifier-2 proteins in a time-dependent manner. We found the production of Th1 cytokines (IFN-γ and TNF-α) and the transcription of NF-κB/p65 were promoted by overexpression and inhibited by interference of small ubiquitin-related modifier-2. In addition, we showed that small ubiquitin-related modifier-2 can inhibit intracellular survival of Brucella abortus 2308 by regulating activation of the NF-κB pathway. Taken together, this work shows that small ubiquitin-related modifier-2 modification of NF-κB2/p65 is essential for the survival of Brucella abortus 2308 inside macrophages. This work may help to unravel the pathogenic mechanisms of Brucella infections.

Syphilis is an important health problem worldwide; however, few studies have probed the impact of syphilitic infection on T cell turnover. The mechanisms behind the frequency of T cell subset changes and the associations between these subsets during syphilitic infection remain unclear. Herein, we used a cell-staining method and flow cytometry to explore changes in T cell subpopulations and potential contribution of apoptosis and pyroptosis that triggered therein. We investigated caspase-1-mediated pyroptosis and caspase-3-mediated apoptosis of CD4⁺ and CD8⁺ T cells, the major effector lymphocytes with pivotal roles in the pathogenesis of infectious diseases. We found that the levels of caspase-1 and caspase-3 increased in both the circulation and intracellularly in CD4⁺ and CD8⁺ T cells. Caspase-1 showed a continual increase from early latent stage infection through to phase 2 disease, whereas caspase-3 increased through to phase 1 disease but declined during phase 2. In addition, serum levels and intracellular expression of caspase-1 and caspase-3 were positively correlated. Overall, this study increases our understanding of how syphilitic infection influences CD4⁺ and CD8⁺ T-cell turnover, which may help with designing novel and effective strategies to control syphilis infection and prevent its transmission.

Our aim was to analyze whether endotoxemia, i.e. translocation of LPS to circulation, is reflected in the serum metabolic profile in a general population and in participants with cardiometabolic disorders. We investigated three Finnish cohorts separately and in a meta-analysis (n = 7178), namely population-based FINRISK97, FinnTwin16 consisting of young adult twins, and Parogene, a random cohort of cardiac patients. Endotoxemia was determined as serum LPS activity and metabolome by an NMR platform. Potential effects of body mass index (BMI), smoking, metabolic syndrome (MetS), and coronary heart disease (CHD) status were considered. Endotoxemia was directly associated with concentrations of VLDL, IDL, LDL, and small HDL lipoproteins, VLDL particle diameter, total fatty acids (FA), glycoprotein acetyls (GlycA), aromatic and branched-chain amino acids, and Glc, and inversely associated with concentration of large HDL, diameters of LDL and HDL, as well as unsaturation degree of FAs. Some of these disadvantageous associations were significantly stronger in smokers and subjects with high BMI, but did not differ between participants with different CHD status. In participants with MetS, however, the associations of endotoxemia with FA parameters and GlycA were particularly strong. The metabolic profile in endotoxemia appears highly adverse, involving several inflammatory characters and risk factors for cardiometabolic disorders.

In this study, we aim to investigate the role of miR-30a-5p in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) using LPS-induced A549 cells and mice. We found cell viability was significantly declined accompanied by cell apoptosis and cell cycle arrest at G0/G1 phase in LPS-treated A549 cells. MiR-30a-5p was down-regulated by LPS treatment and miR-30a-5p significantly protected A549 cells from LPS-induced injury by increasing cell viability, reducing cell apoptosis, promoting cell cycle progression, and inhibiting inflammatory reactions. Dual-luciferase activity demonstrated that RUNX2 was a direct target for miR-30a-5p and its expression was negatively and directly regulated by miR-30a-5p. Over-expression of RUNX2 weakened the inhibitory effect of miR-30a-5p on inflammatory injury. In vivo, over-expression of miR-30a-5p alleviated LPS-induced inflammatory responses and lung injury in LPS-administrated mice. Besides, miR-30a-5p repressed LPS-elevated phosphorylation levels of the signal transducer and activator of transcription 3 (STAT3) and c-Jun N-terminal kinase (JNK), IκBα degradation, and NF-κB p65 phosphorylation. In conclusion, miR-30a-5p ameliorates LPS-induced inflammatory injury in A549 cells and mice via targeting RUNX2 and related signaling pathways, thereby influencing the progression of ARDS.

In this comparative study, serum complement system antimicrobial activity was measured from 159 serum samples, taken from individuals from microbe-damaged (70 samples) and from reference buildings (89 samples). Antimicrobial activity was assessed using a probe-based bacterial Escherichia coli-lux bioluminescence system and comparison was made at a group level between the experimental and reference group. The complement activity was higher in users of microbe-damaged buildings compared with the reference group and the significant (P < 0.001) increase in activity was found in the classical reaction pathway. This study strengthens our notion that exposure to indoor-related microbe damage increases the risk for systemic subclinical inflammation and creates a health risk for building users.