Innate Immunity最新文献

Extracellular vesicles (EVs), which are nanosized membranous structures released by diverse cell types, serve as crucial mediators of intercellular communication. Recent evidence has highlighted the dynamic transfer of various biological components, including proteins, lipids, mRNAs, non-coding RNAs, miRNAs, and DNA, via EVs. Immuno-stimulated cells actively release EVs that play a pivotal role in regulating the innate immune system. This study comprehensively reviews the current scientific findings, shedding light on the intricate biological roles of EVs in regulating innate immune cells and the overall immune system. This discussion encompasses diverse pathophysiological conditions and provides valuable insights into the multifaceted contributions of EVs to innate immune responses.

The type I interferon family of cytokines are rapidly produced following innate pattern recognition receptor engagement and establish a critical early state of host defense. Type I interferons act in antiviral immunity as transcriptional activators and the binding of any type I interferon to the common IFNAR receptor triggers the transcription of Interferon Stimulated Genes (ISGs). A defined set of ISGs have been described through exhaustive studies and the protein products of these ISGs function to increase cell intrinsic resistance to viral growth and to promote viral clearance. Simultaneously, interferons also drive a much less well studied program of transcriptional suppression, inhibiting the expression of an unknown number of genes, with poorly understood consequences for disease. The limited number of genes currently known to be transcriptionally suppressed by IFN are enriched for those with immune-mediating activities such as inflammatory cytokines (e.g., IL-1β), cytokine receptors (e.g., IFNγR) and chemokines. Interferon dependent transcriptional suppression of immune response genes is therefore thought to underlie the immune suppression associated with interferon production during many bacterial infections (e.g., mycobacterium tuberculosis and listeria monocytogenes) and may also explain the palliative effects of interferons in some autoimmune diseases. Despite the health relevance of IFN driven transcriptional suppression, no consensus molecular model exists to explain its selectivity or regulation. In this review we highlight the current literature detailing the known targets of IFN transcriptional suppression within the various disease models in which it has been observed. We also review the relevant molecular mechanisms which have been proposed to explain transcriptional suppression by interferons and discuss the remaining open questions in this field with an ambition to stimulate future work in this area.

The gut microbiota plays a crucial role in various physiological functions, such as the production of microbial compounds and maintaining homeostatic equilibrium by complex host-microbial interactions. However, any shift in the constitution and diversity of the microbiota or abnormal interaction with the host can prompt the development of dysbiosis. This review thus illustrates that microbial metabolites, notably short-chain fatty acids, tryptophan metabolites, bile acids, and polyamines, exert significant regulatory effects on innate and adaptive immunological processes, immune response and intestinal barrier integrity through specific receptor activation, involving TLRs, NODs, GPCRs, nuclear receptors, and Wnt/β-catenin. It further explores the disruption of host signalling pathways, caused by dysbiosis, promoting the transcription of specific genes and activating pro-inflammatory pathways. Consequently, this suggests that microbiota acts beyond general health, eventually contributing to gastrointestinal, metabolic, and neurological disorders. Lastly, this review highlights therapeutic approaches required to restore balance and uphold physiological balance.

The formation of neutrophil extracellular traps (NETs) is known as an important part of the innate immune response. Still, some mechanisms regarding their formation and role during a disease are not completely understood yet. To visualize NETs by immunofluorescence microscopy, a chemical fixation is required. Therefore, this study focused on the effect of chemical fixatives on immunofluorescence staining of selected neutrophil and NET-markers, including myeloperoxidase (MPO), DNA/histone-1-complexes and citrullinated histone H3 (H3cit). Neutrophils isolated from fresh human blood were stimulated with phorbol-12-myristate 13-acetate (PMA) to induce NETs and fixed with paraformaldehyde (PFA, 4%), glutardialdehyde (GA, 5%) or methanol (MeOH, 100%) using different incubation times depending on the used fixative. We found that different fixation times with PFA had no effect on the staining intensity of MPO or DNA/histone-1-complex antibodies. For the staining of H3cit, fixation with PFA for 24 h decreased the signal intensity whereas 30 min fixation time had no effect. In contrast, glutardialdehyde induced a high amount of autofluorescence, and the fixation with 100% MeOH resulted in visible cellular damage. Therefore, we recommend 15-30 min PFA fixation for the respective stainings. Our results provide a solid basis for future experiments to study neutrophil activation and NET-formation.

A previous study found that repeated intrauterine infusions of lipopolysaccharide (LPS) followed by an LPS infusion into the mammary glands attenuated the mammary inflammatory response. This suggests that repeated LPS infusion into the uterus promotes endotoxin tolerance (ET) in the mammary gland. However, the specific changes in mammary glands under ET conditions remain unclear. We hypothesized that ET affects leukocyte function in milk. This study aimed to investigate leukocyte function in milk under ET conditions induced through repeated LPS infusions into the uterus for three days followed by LPS infusion into the mammary glands of goats. Goats in the IU group (n = 17) received an infusion of 100 μg LPS in 5 ml saline into the uterus for three consecutive days (d -3, -2, and -1), whereas the goats in the control group did not receive this infusion (n = 19). On d 0, 1 μg LPS in 5 ml saline was infused into the mammary glands of both groups. Milk was collected 0, 4, 8, 12, 24, 48, 72, and 120 h after LPS intramammary infusion. The IU group decreased cytokine production (interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-1Ra) in milk following intramammary LPS infusion. Moreover, leukocyte activation, measured by phagocytic activity and CD11b expression, was higher in the IU group than in the control group. These findings suggest that goats exhibit enhanced leukocyte function in mammary glands under ET conditions, induced by repeated intrauterine infusion of LPS.

This study investigates the expression of RIG-I-like receptors (RLRs) - RIG-I, MDA5, and LGP2 - in Lagovirus europaeus/GI.2 infections causing Rabbit Hemorrhagic Disease. Despite over 30 years of study, the acute pathogenesis remains incompletely understood. Lack of in vitro culture systems hampers vaccine development. The experiment, conducted on European rabbits, reveals a significant increase in RLR expression during infection, particularly in organs associated with severe pathology. The findings suggest a pivotal role for RLRs, especially RIG-I, in the host's defense against Lagovirus europaeus. Further research is needed to unravel the complete molecular pathway and associated factors, offering potential insights for therapeutic interventions.

Background: We aimed to investigate the potential of altered levels of various acute phase proteins (APPs) in the plasma, either used alone or in combination with ultrasound-, clinical-, and conventional blood-based tests, for predicting the risk of intra-amniotic inflammation (IAI), microbial invasion of the amniotic cavity (MIAC), histologic chorioamnionitis (HCA), and funisitis in women with preterm premature rupture of membranes (PPROM).

Methods: A total of 195 consecutive pregnancies involving singleton women with PPROM (at 23 + 0-34 + 0 weeks) who underwent amniocentesis and from whom plasma samples were obtained at amniocentesis were retrospectively included in this study. Amniotic fluid (AF) was cultured to assess the MIAC and analyzed for interleukin (IL)-6 levels to define IAI (AF IL-6 level of ≥2.6 ng/mL). The plasma concentrations of hepcidin, mannose-binding lectin (MBL), pentraxin-2, retinol-binding protein 4 (RBP4), serum amyloid A1 (SAA1), and serpin A1 were determined using ELISA. Ultrasonographic cervical length (CL), neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein levels were measured. IAI/MIAC was defined as IAI, MIAC, or both.

Results: Multivariate logistic regression analyses showed the following: (1) elevated plasma levels of hepcidin and SAA1 and decreased levels of RBP4 in the plasma were independently associated with IAI/MIAC and (2) decreased plasma RBP4 levels were independently associated with funisitis; however, (3) none of the plasma APPs investigated were associated with acute HCA when adjusted for baseline covariates. Using stepwise regression analysis, noninvasive prediction models comprising plasma RBP4 levels, CL, NLR, and gestational age at sampling were proposed, which provided a good prediction of IAI/MIAC and funisitis (area under the curve: 0.80 and 0.72, respectively).

Conclusions: Hepcidin, RBP4, and SAA1 were identified as potential APP biomarkers in the plasma predictive of IAI/MIAC or funisitis in patients with PPROM. In particular, combination of these APP biomarkers with ultrasound-, clinical-, and conventional blood-based markers can significantly support the diagnosis of IAI/MIAC and funisitis.

Background: Globally, colorectal cancer (CRC) is among the most prevalent malignant tumors. It is characterized by unlimited proliferation, invasion, and metastasis. MicroRNA-126 (miR-126) has been shown in many studies to play a significant role in CRC, but data regarding its role in CRC Egyptian patients are limited.

Objectives: This case-control study aimed to investigate the miR-126 as a potential marker in CRC Egyptian patients and to correlate its expression levels with CRC tumor, node, metastasis (TNM) stage, distant metastasis, and tumor size.

Methods: The study included 50 adult Egyptian participants (30 patients with CRC, 10 patients with colorectal adenoma as a pathological control, and 10 healthy controls). MiR-126 expression levels were detected using Real-Time Quantitative PCR (qPCR) along with the endogenous reference gene hsa-miR-103a in all participants.

Results: MiR-126 expression was significantly decreased in CRC patients than both control groups. It was associated with advanced TNM stage (p = 0.001) and distant metastasis (p = 0.002). However, it was not correlated with tumor size (p = 0.980), carcinoembryonic antigen (CEA) (p = 0.397), and cancer antigen 19-9 (CA19-9) (p = 0.236). The best cut-off point of miR-126 to discriminate CRC from both controls was 0.7 and to discriminate metastatic CRC from non-metastatic CRC was 0.3.

Conclusions: Our results suggest that miR-126 could be used as an early marker for CRC detection among Egyptian patients and a good prognostic indicator associated with metastasis.

The role of macrophage (MØ) cellular metabolism and reprogramming during TB infection is of great interest due to the influence of Mycobacterium spp. on MØ bioenergetics. Recent studies have shown that M. tuberculosis induces a TLR2-dependent shift towards aerobic glycolysis, comparable to the established LPS induced pro-inflammatory M1 MØ polarisation. Distinct differences in the metabolic profile of murine and human MØ indicates species-specific differences in bioenergetics. So far, studies examining the metabolic potential of bovine MØ are lacking, thus the basic bioenergetics of bovine and human MØ were explored in response to a variety of innate immune stimuli. Cellular energy metabolism kinetics were measured concurrently for both species on a Seahorse XFe96 platform to generate bioenergetic profiles for the response to the bona-fide TLR2 and TLR4 ligands, FSL-1 and LPS respectively. Despite previous reports of species-specific differences in TLR signalling and cytokine production between human and bovine MØ, we observed similar respiratory profiles for both species. Basal respiration remained constant between stimulated MØ and controls, whereas addition of TLR ligands induced increased glycolysis, as measured by the surrogate parameter ECAR. In contrast to MØ stimulation with M. tuberculosis PPD, another TLR2 ligand, M. bovis PPD treatment significantly enhanced basal respiration rates and glycolysis only in human MØ. Respiratory profiling further revealed significant elevation of ATP-linked OCR and maximal respiration suggesting a strong OXPHOS activation upon M. bovis PPD stimulation in human MØ. Our results provide an exploratory set of data elucidating the basic respiratory profile of bovine vs. human MØ that will not only lay the foundation for future studies to investigate host-tropism of the M. tuberculosis complex but may explain inflammatory differences observed for other zoonotic diseases.