Pro-inflammatory Immunity Research Articles

Obstructive sleep apnea alters microRNA levels: Effects of continuous positive airway pressure.

Obstructive sleep apnea (OSA) has been linked to cytokine-mediated chronic inflammatory states. Continuous positive airway pressure (CPAP) is an established therapy for OSA, but its effects on inflammation remain unclear. A recent study from our group identified soluble cytokine receptors altered in OSA patients and modified by CPAP adherence. However, the upstream regulatory pathways responsible for these shifts in proinflammatory cascades with OSA and CPAP therapy remained unknown. Accordingly, this study mapped OSA and CPAP-modulated soluble cytokine receptors to specific microRNAs and then tested the hypothesis that OSA and CPAP adherence shift cytokine-related microRNA expression profiles. Plasma samples were collected from patients with OSA (n=50) at baseline and approximately 90 days after CPAP initiation and compared to referent control subjects (n=10). Patients with OSA were further divided into cohorts defined by adherence vs nonadherence to CPAP therapy. The microRNAs that mapped to soluble cytokine receptors of interest were subjected to quantitative polymerase chain reaction. At baseline, increased hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-5p, hsa-miR-195-5p, hsa-miR-424-5p, hsa-miR-223-3p, and hsa-miR-223-5p were observed in patients with OSA compared to controls (p<0.05). In CPAP adherent patients (n=22), hsa-miR233-3p and hsa-miR233-5p decreased at follow-up (p<0.05) whereas there was no change in miR levels from baseline in non-adherent CPAP patients (n=28). The miRs hsa-miR233-3p and hsa-miR233-5p mapped to both proinflammatory and innate immunity activation; the inflammasome. A specific set of microRNAs, including hsa-miR233-3p and hsa-miR233-5p, may serve as a marker of inflammatory responses in patients with OSA, and be used to assess attenuation of inflammasome activation by CPAP.

Single-cell chromatin accessibility and transcriptomic characterization of Behcet’s disease

Behect’s disease is a chronic vasculitis characterized by complex multi-organ immune aberrations. However, a comprehensive understanding of the gene-regulatory profile of peripheral autoimmunity and the diverse immune responses across distinct cell types in Behcet’s disease (BD) is still lacking. Here, we present a multi-omic single-cell study of 424,817 cells in BD patients and non-BD individuals. This study maps chromatin accessibility and gene expression in the same biological samples, unraveling vast cellular heterogeneity. We identify widespread cell-type-specific, disease-associated active and pro-inflammatory immunity in both transcript and epigenomic aspects. Notably, integrative multi-omic analysis reveals putative TF regulators that might contribute to chromatin accessibility and gene expression in BD. Moreover, we predicted gene-regulatory networks within nominated TF activators, including AP-1, NF-kB, and ETS transcript factor families, which may regulate cellular interaction and govern inflammation. Our study illustrates the epigenetic and transcriptional landscape in BD peripheral blood and expands understanding of potential epigenomic immunopathology in this disease.

Association of Chronic Toxoplasma gondii Infection with Pro-Inflamatory Cytokine Interleukin (IL)-12 Responses in Type-2 Diabetes Mellitus Patients of Bangladesh.

Toxoplasma gondii is an intracellular protozoan parasite that causes toxoplasmosis in around one-third of the world population, particularly in pregnant women and immunocompromised individuals. Diabetes mellitus (DM) is one of the most severe global health challenges in the 21st century, and especially, type-2 diabetes mellitus (T2DM) accounts for 90% of the diabetes cases diagnosed globally. In Bangladesh, the rate of T2DM is rising gradually with the improvement in living standards. The aim of this study is to find out the correlation between latent toxoplasmosis and T2DM, emphasizing the pro-inflammatory cytokine immunity. For this, 100 (N = 100) patients with T2DM and 100 (N = 100) healthy controls were enrolled to determine the seroprevalence of toxoplasmosis using enzyme-linked immunosorbent assay (ELISA). In addition, ELISA was also performed to determine the level of pro-inflammatory cytokine, interleukin (IL)-12, to understand its role in the development of toxoplasmosis. In our study, 39.39% of the T2DM patients were positive with anti-T. gondii Immunoglobulin G by ELISA, whereas the rate of seropositivity in healthy controls was 39.73%. We did not find significant association between T. gondii infection and T2DM, but our data confirmed a high prevalence of chronic toxoplasmosis in Bangladeshi population. From hematology tests, it was found that the T2DM patients had significantly lower levels of total white blood cells (P = 0.0015), circulating eosinophils (P = 0.0026), and neutrophils (P = 0.0128) than the healthy controls. On the other hand, the levels of lymphocytes (P = 0.0204) and monocytes (P = 0.0067) were significantly higher in patients. Furthermore, T. gondii infected T2DM patients had significantly higher levels of IL-12 than the healthy controls (P = 0.026), suggesting a link between parasitic infection and IL-12 secretion. Further studies are to be performed to find out the exact cause of high prevalence of chronic T. gondii infection in Bangladeshi population.

Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy.

Radiation necrosis, also known as treatment-induced necrosis, has emerged as an important adverse effect following stereotactic radiotherapy (SRS) for brain metastases. The improved survival of patients with brain metastases and increased use of combined systemic therapy and SRS have contributed to a growing incidence of necrosis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway (cGAS-STING) represents a key biological mechanism linking radiation-induced DNA damage to pro-inflammatory effects and innate immunity. By recognizing cytosolic double-stranded DNA, cGAS induces a signaling cascade that results in the upregulation of type 1 interferons and dendritic cell activation. This pathway could play a key role in the pathogenesis of necrosis and provides attractive targets for therapeutic development. Immunotherapy and other novel systemic agents may potentiate activation of cGAS-STING signaling following radiotherapy and increase necrosis risk. Advancements in dosimetric strategies, novel imaging modalities, artificial intelligence, and circulating biomarkers could improve the management of necrosis. This review provides new insights into the pathophysiology of necrosis and synthesizes our current understanding regarding the diagnosis, risk factors, and management options of necrosis while highlighting novel avenues for discovery.

Chicken Glycogen Synthase Kinase 3β Suppresses Innate Immune Responses and Enhances Avian Leukosis Virus Replication in DF-1 Cells.

Glycogen synthase kinase 3β (GSK3β) is a widely distributed multifunctional serine/threonine kinase. In mammals, GSK3β regulates important life activities such as proinflammatory response, anti-inflammatory response, immunity, and cancer development. However, the biological functions of chicken GSK3β (chGSK3β) are still unknown. In the present study, the full-length cDNA of chGSK3β was first cloned and analyzed. Absolute quantification of chicken chGSK3β in 1-day-old specific-pathogen-free birds has shown that it is widely expressed in all tissues, with the highest level in brain and the lowest level in pancreas. Overexpression of chGSK3β in DF-1 cells significantly decreased the gene expression levels of interferon beta (IFN-β), IFN regulatory factor 7 (IRF7), Toll-like receptor 3 (TLR3), melanoma differentiation-associated protein 5 (MDA5), MX-1, protein kinase R (PKR), and oligoadenylate synthase-like (OASL), while promoting the replication of avian leukosis virus subgroup J (ALV-J). Conversely, levels of most of the genes detected in this study were increased when chGSK3β expression was knocked down using small interfering RNA (siRNA), which also inhibited the replication of ALV-J. These results suggest that chGSK3β plays an important role in the antiviral innate immune response in DF-1 cells, and it will be valuable to carry out further studies on the biological functions of chGSK3β. IMPORTANCE GSK3β regulates many life activities in mammals. Recent studies revealed that chGSK3β was involved in regulating antiviral innate immunity in DF-1 cells and also could positively regulate ALV-J replication. These results provide new insights into the biofunction of chGSK3β and the virus-host interactions of ALV-J. In addition, this study provides a basis for further research on the function of GSK3 in poultry.

Nlrp12 deficiency alters gut microbiota and ameliorates Faslpr -mediated systemic autoimmunity in male mice.

NLRP12 has dual roles in shaping inflammation. We hypothesized that NLRP12 would modulate myeloid cells and T cell function to control systemic autoimmunity. Contrary to our hypothesis, the deficiency of Nlrp12 in autoimmune-prone B6.Faslpr/lpr mice ameliorated autoimmunity in males but not females. Nlrp12 deficiency dampened B cell terminal differentiation, germinal center reaction, and survival of autoreactive B cells leading to decreased production of autoantibodies and reduced renal deposition of IgG and complement C3. In parallel, Nlrp12 deficiency reduced the expansion of potentially pathogenic T cells, including double-negative T cells and T follicular helper cells. Furthermore, reduced pro-inflammatory innate immunity was observed, where the gene deletion decreased in-vivo expansion of splenic macrophages and mitigated ex-vivo responses of bone marrow-derived macrophages and dendritic cells to LPS stimulation. Interestingly, Nlrp12 deficiency altered the diversity and composition of fecal microbiota in both male and female B6/lpr mice. Notably, however, Nlrp12 deficiency significantly modulated small intestinal microbiota only in male mice, suggesting that the sex differences in disease phenotype might be gut microbiota-dependent. Together, these results suggest a potential pathogenic role of NLRP12 in promoting systemic autoimmunity in males. Future studies will investigate sex-based mechanisms through which NLRP12 differentially modulates autoimmune outcomes.

T-cell dysregulation and inflammatory process in Gcn2 (Eif2ak4-/-)-deficient rats in basal and stress conditions.

Hereditary pulmonary veno-occlusive disease (hPVOD) is a severe form of autosomal recessive pulmonary hypertension and is due to biallelic loss of function of the EIF2AK4 gene (alias GCN2) coding for GCN2. GCN2 is a stress kinase that belongs to the integrated stress response pathway (ISR). Three rat lines carrying biallelic Gcn2 mutation were generated and found phenotypically normal and did not spontaneously develop a PVOD-related disease. We submitted these rats to amino acid deprivation to document the molecular and cellular response of the lungs and to identify phenotypic changes that could be involved in PVOD pathophysiology. Gcn2-/- rat lungs were analyzed under basal conditions and 3 days after a single administration of PEG-asparaginase (ASNase). Lung mRNAs were analyzed by RNAseq and single-cell RNAseq (scRNA-seq), flow cytometry, tissue imaging, and Western blots. The ISR was not activated after ASNase treatment in Gcn2-/- rat lungs, and apoptosis was increased. Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area. Under basal conditions, scRNA-seq analysis of Gcn2-/- rat lungs revealed increases in two T-cell populations, a LAG3+ T-cell population and a proliferative T-cell population. Following ASNase administration, we observed an increase in calprotectin expression involved in TLR pathway activation and neutrophil infiltration. In conclusion, under basal and asparagine and glutamine deprivation induced by asparaginase administration, Gcn2-/- rats display molecular and cellular signatures in the lungs that may indicate a role for Gcn2 in immune homeostasis and provide further clues to the mechanisms of hPVOD development.

A miRNA-based gene therapy nanodrug synergistically enhances pro-inflammatory antitumor immunity against melanoma

MicroRNA (miRNA)-based gene therapy is a robust approach to treating human cancers. However, the low target specificity and safety issues associated with viral vectors have limited the clinical use of miRNA therapeutics. In the present study, we aimed to develop a biocompatible nanocarrier to deliver the tumor suppressor miR-30a-5p for gene therapy of ocular melanoma. The quasi-mesoporous magnetic nanospheres (MMNs) were prepared by polyelectrolytes-mediated self-assembling Fe3O4 nanocrystals; the cationic polymer capped quasi-mesoporous inner tunnels of the MMNs facilitate high miRNA loading and protect from nuclease degradation. Then, the outer layer of the MMNs was modified with a disulfide bond bridged very low molecular weight polyethyleneimine (PEI) network to form redox-responsive nanospheres (rMMNs) that enhance the miRNA payload and enable miRNA release under glutathione-dominant tumor microenvironment. The miR-30a-5p loaded rMMNs nanodrug (miR-30a-5p@rMMNs) upregulated miR-30a-5p level and inhibited malignant phenotypes of ocular melanoma by targeting the transcription factor E2F7 both in vitro and in vivo. Additionally, rMMNs act as an enhancer to increase cancer cell apoptosis by modulating M1-like macrophage polarization and activating Fenton reaction. Thus, the rMMNs is a promising miRNA carrier for gene therapy and could enhance pro-inflammatory immunity in melanoma and other cancers. Statement of significance• miR-30a-5p@rMMNs inhibited malignant phenotypes of ocular melanoma both in vitro and in vivo.• The rMMNs promoted M1 macrophage polarization thus synergistically enhancing pro-inflammatory anti-tumor immunity against melanoma.• The rMMNs showed no obvious toxicity under the injection dose.

A Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Assay Identifies Nilotinib as an Inhibitor of Inflammation in Acute Myeloid Leukemia.

Inflammatory responses are important in cancer, particularly in the context of monocyte-rich aggressive myeloid neoplasm. We developed a label-free cellular phenotypic drug discovery assay to identify anti-inflammatory drugs in human monocytes derived from acute myeloid leukemia (AML), by tracking several features ionizing from only 2500 cells using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A proof-of-concept screen showed that the BCR-ABL inhibitor nilotinib, but not the structurally similar imatinib, blocks inflammatory responses. In order to identify the cellular (off-)targets of nilotinib, we performed thermal proteome profiling (TPP). Unlike imatinib, nilotinib and other later-generation BCR-ABL inhibitors bind to p38α and inhibit the p38α-MK2/3 signaling axis, which suppressed pro-inflammatory cytokine expression, cell adhesion, and innate immunity markers in activated monocytes derived from AML. Thus, our study provides a tool for the discovery of new anti-inflammatory drugs, which could contribute to the treatment of inflammation in myeloid neoplasms and other diseases.

Most reactions leading to neuropathic pain at dorsal root ganglion of rats with spinal nerve ligation have occurred in the early phase

In order to study the mechanism of early and late neuropathic pain, Ribonucleic acid sequencing (RNA-seq) technique was used to analyze the dorsal root ganglion (DRG) transcriptome of rat induced by spinal nerve ligation (SNL). It was found that most of the reactions leading to neuropathic pain at dorsal root ganglion, such as pro-inflammatory response and immunity, occurred in the early phase.378 genes are up-regulated and 42 genes are down-regulated in the early phase, while in the late phase, there are 27 up-regulated genes and 23 down-regulated genes. Four new pain related genes are found: Cd8a, Bub1b, Ccna2 and Cdk1. From the analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) functions enriched by differentially expressed genes (DEGs), dorsal root ganglion should carry out immunities, pro-inflammations and related compensatory regulation in response to peripheral nerve injury in the early phase. The late phase is characterized by maintaining long-term or chronic inflammation.

Blood RNA Sequencing Indicates Upregulated BATF2 and LY6E and Downregulated ISG15 and MT2A Expression in Children with Autism Spectrum Disorder.

Mutations in over 100 genes are implicated in autism spectrum disorder (ASD). DNA SNPs, CNVs, and epigenomic modifications also contribute to ASD. Transcriptomics analysis of blood samples may offer clues for pathways dysregulated in ASD. To expand and validate published findings of RNA-sequencing (RNA-seq) studies, we performed RNA-seq of whole blood samples from an Israeli discovery cohort of eight children with ASD compared with nine age- and sex-matched neurotypical children. This revealed 10 genes with differential expression. Using quantitative real-time PCR, we compared RNAs from whole blood samples of 73 Israeli and American children with ASD and 26 matched neurotypical children for the 10 dysregulated genes detected by RNA-seq. This revealed higher expression levels of the pro-inflammatory transcripts BATF2 and LY6E and lower expression levels of the anti-inflammatory transcripts ISG15 and MT2A in the ASD compared to neurotypical children. BATF2 was recently reported as upregulated in blood samples of Japanese adults with ASD. Our findings support an involvement of these genes in ASD phenotypes, independent of age and ethnicity. Upregulation of BATF2 and downregulation of ISG15 and MT2A were reported to reduce cancer risk. Implications of the dysregulated genes for pro-inflammatory phenotypes, immunity, and cancer risk in ASD are discussed.

Association of peptidoglycan recognition protein 1 to post-myocardial infarction and periodontal inflammation: A subgroup report from the PAROKRANK (Periodontal Disease and the Relation to Myocardial Infarction) study.

Peptidoglycan recognition protein 1 (PGLYRP1) is an antimicrobial and proinflammatory innate immunity protein activated during infections. We aimed to investigate whether PGYLRP1 and associated molecules of the immune response in saliva is a cumulative outcome result of both MI and periodontal inflammation. Two hundred patients with MI and another 200 matched non-MI controls were included. A full-mouthexamination was conducted to assess periodontal inflammation and collection of stimulated saliva was performed 6 to 10weeks after the first MI. PGLYRP1, triggering receptor expressed on myeloid cells 1(TREM-1), interleukin-1 beta (IL-1β) were analyzed by ELISA. Matrix metalloproteinase (MMP)-8 levels were determined by IFMA. Compared to controls, MI patients showed higher salivary PGLYRP1, but not TREM-1 levels. The difference in PGLYRP1 levels remained after adjustment for covariates. In MI patients, the PGLYRP1 levels positively correlated with BOP and PPD 4 to 5mm. Among non-MI subjects, the levels of PGLYRP1 correlated positively and significantly with BOP and total PPD. Salivary PGLYRP1 concentrations also showed strong positive correlations with levels of TREM-1, IL-1β and MMP-8. In multivariate linear regression analysis, in MI patients, BOP and former smokingstatus displayed an association with salivary PGLYRP1 concentration. MI patients showed higher salivary PGLYRP1 levels than healthy controls, also after adjusting for smoking, sex, age and periodontal health status. Salivary levels of PGLYRP1 may reflect the overall inflammatory burden to chronic bacterial exposure, possibly underpinning the observed associations between periodontitis and exposure with MI.

Effects of N-acylation on the immune adjuvanticity of analogs of the Quillaja saponins derivative GPI-0100

Modification of the 3-glucuronic acid (GlcA) residue from the Quillaja saponin (QS) adjuvants by N-acylation, yields derivatives with linear alkylamides that show structural and functional changes. Structural, since the relatively unreactive added hydrophobic alkyl chains may modify these glycosides’ conformation and micellar structure. Functional, because altering the availability of proposed pharmacophores, like fucose (Fucp) and aldehyde groups, to interact with their cellular receptors, may change these glycosides’ adjuvanticity. While deacylated QS (DS-QS) adjuvants bias the response toward a sole anti-inflammatory Th2 immunity against an antigen, their N-alkylated derivatives carrying octyl to dodecylamide residues, modify that response to a pro-inflammatory Th1 immunity. As shown by their IgG2a/IgG1 titer ratios, which are higher than those for Th2 immunity. A result of the fact that in mice, the IgG2a levels are dependent on the direct influence of secreted interferon-γ (IFN-γ), a crucial Th1 cytokine. But addition of the longer and more lipophilic tetradecylamide group, yields derivatives that like DS-QS induce Th2 immunity, as shown by their low IgG2a/IgG1 ratio. Results that imply that changes in these analogs’ conformation and micellar structure, would affect the immunomodulatory properties or adjuvanticity of N-acylated DS-QS. Physical changes that may alter the availability of groups like Fucp, to bind to its presumed dendritic cells’ lectin receptor DC-SIGN; an essential step in the stimulation of Th2 immunity. Structural properties that in an aqueous environment, would depend on these glycosides’ balance of their hydrophilic and lipophilic moieties (HLB), and the interactions of the newly introduced alkyl chain with the native QS’ lipophilic triterpene aglycone and hydrophilic oligosaccharide chains. A situation that would explain these new derivatives’ qualitative and quantitative changes in adjuvanticity.

CD4+ T cell effector activities accelerate Alzheimer's disease pathologies.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairments linked to pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered beginning early and extending throughout the disease. How these occurs and whether they can be harnessed to affect disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teff) serving to drive pro-inflammatory and neurodestructive immunity. Here, we investigated the role of effector immunity could affect cellular level disease pathobiology in an AD animal model. Aβ-specific Th1 and Th17 Teff were induced by Aβ-immunization of donors, CD4+ T cells isolated, expanded by selective culture in the presence of Aβ, and cloned as monoclonal Teff lines. Aβ-specific Th1 and Th17 Teff were adoptively transferred into the APP/PS1 double transgenic mice. Three weeks after transfer, radial arm water maze (RAWM), biochemical, immunohistochemical and transcriptomic tests assessed memory functions, pathologies, and mechanism. Development of stable monoclonal Aβ-Th1 and Aβ-Th17 cells was verified by specific cytokine signatures, nuclear transcription factors and haplotype matched major histocompatibility-II (MHCII)-Aβ tetramer staining. Accelerated memory impairments were observed in APP/PS1 mice that received Aβ-specific Teffs. Both Aβ-Th1 and Aβ-Th17 cells significantly induced pro-inflammatory cytokines TNF-α, IFN-γ and IL-17 and transcription factors Tbet and RORγ compared to controls in the periphery. Aβ load significantly increased while synaptic plasticity decreased in the brain of AD mice received Aβ-Th1 cells. Aβ-Teff driven systemic inflammatory responses were attributed to the decreased numbers and functions of regulatory T cells (Treg) in both the CNS and periphery. Additionally, transferred Aβ-Teff increased microglia reactivity and neuroinflammatory activities in the affected brain regions. Autoreactive Aβ-Teff transform a pro-inflammatory microenvironment accelerating AD pathology. This is sped by limiting Treg activities. Control of this neurodestructive environment represents a potential therapeutic strategy and can be sped by augmenting peripheral Treg numbers and function. Similar therapeutic ends have been shown to be efficacious in both pre-clinical and clinical trials in related neurodegenerative disorders.

CD4+ effector T cells accelerate Alzheimer\u2019s disease in mice

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model.MethodsIn this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb–KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses.ResultsThe propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system.ConclusionsThese results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs.Graphical

Maternal Monocytes Respond to Cell-Free Fetal DNA and Initiate Key Processes of Human Parturition.

Throughout gestation, the maternal immune system is tightly modulated to allow growth of a semiallogeneic fetus. During the third trimester, the maternal immune system shifts to a proinflammatory phenotype in preparation for labor. What induces this shift remains unclear. Cell-free fetal DNA (cffDNA) is shed by the placenta and enters maternal circulation throughout pregnancy. Levels of cffDNA are increased as gestation progresses and peak before labor, coinciding with a shift to proinflammatory maternal immunity. Furthermore, cffDNA is abnormally elevated in plasma from women with complications of pregnancy, including preterm labor. Given the changes in maternal immunity at the end of pregnancy and the role of sterile inflammation in the pathophysiology of spontaneous preterm birth, we hypothesized that cffDNA can act as a damage-associated molecular pattern inducing an inflammatory cytokine response that promotes hallmarks of parturition. To test this hypothesis, we stimulated human maternal leukocytes with cffDNA from primary term cytotrophoblasts or maternal plasma and observed significant IL-1β and CXCL10 secretion, which coincides with phosphorylation of IFN regulatory factor 3 and caspase-1 cleavage. We then show that human maternal monocytes are crucial for the immune response to cffDNA and can activate bystander T cells to secrete proinflammatory IFN-γ and granzyme B. Lastly, we find that the monocyte response to cffDNA leads to vascular endothelium activation, induction of myometrial contractility, and PGE2 release in vitro. Our results suggest that the immune response to cffDNA can promote key features of the parturition cascade, which has physiologic consequences relevant to the timing of labor.

Longitudinal evidence for immunosenescence and inflammaging in free-living great tits.

The first-line effector mechanisms of immune defence, including inflammation and oxidative burst, contribute significantly to host-pathogen resistance. Whether these immune responses undergo age-related changes in birds remains unknown. Here, we tracked selected inflammatory parameters in 54 free-living great tits (Parus major) of known age, captured repeatedly over three consecutive years, with the aims to investigate long-term repeatability and age-dependent changes in cellular oxidative burst responsiveness upon in vitro stimulation with bacterial lipopolysaccharide (LPS), and to identify its relationships with leukotriene B4 (LTB4) levels and haematological traits. In addition, we linked these immunological traits to selected physiological markers (antioxidants and oxidative stress markers). LTB4 levels increased with age and we have shown a similar non-significant tendency also for absolute granulocyte counts, indicating propagating chronic inflammation over the bird's lifetime, consistent with the inflammaging hypothesis. In contrast, cellular oxidative burst followed a quadratic trend of dependency on age with a peak in midlife individuals, in line with the immunosenescence hypothesis. Interestingly, LTB4 levels were positively associated with general oxidative damage, but negatively with antioxidant glutathione peroxidase activity, indicating links to redox balance. This longitudinal study demonstrates the contrasting patterns of age-related changes in background and acute markers of pro-inflammatory immunity contributing to immunosenescence in birds and thus provides basis for interpretation of the tested inflammatory markers in cross-cohort datasets.

Recent Updates and Advances in Winiwarter-Buerger Disease (Thromboangiitis Obliterans): Biomolecular Mechanisms, Diagnostics and Clinical Consequences.

Thromboangiitis obliterans (TAO) or Buerger’s disease is a segmental inflammatory, thrombotic occlusive peripheral vascular disease with unknown aetiology that usually involves the medium and small-sized vessels of young male smokers. Due to its unknown aetiology and similarities with atherosclerosis and vasculitis, TAO diagnosis is still challenging. We aimed to review the status of biomolecular and laboratory para-clinical markers in TAO compared to atherosclerosis and vasculitis. We reported that, although some biomarkers might be common in TAO, atherosclerosis, and vasculitis, each disease occurs through a different pathway and, to our knowledge, there is no specific and definitive marker for differentiating TAO from atherosclerosis or vasculitis. Our review highlighted that pro-inflammatory and cell-mediated immunity cytokines, IL-33, HMGB1, neopterin, MMPs, ICAM1, complement components, fibrinogen, oxidative stress, NO levels, eNOS polymorphism, adrenalin and noradrenalin, lead, cadmium, and homocysteine are common markers. Nitric oxide, MPV, TLRs, MDA, ox-LDL, sST2, antioxidant system, autoantibodies, and type of infection are differential markers, whereas platelet and leukocyte count, haemoglobin, lipid profile, CRP, ESR, FBS, creatinine, d-dimer, hypercoagulation activity, as well as protein C and S are controversial markers. Finally, our study proposed diagnostic panels for laboratory differential diagnosis to be considered at first and in more advanced stages.

Washed microbiota transplantation for the treatment of recurrent fungal infection in a patient with ulcerative colitis.

Washed microbiota transplantation for the treatment of recurrent fungal infection in a patient with ulcerative colitis.

Dietary Grape Seed Meal Bioactive Compounds Alleviate Epithelial Dysfunctions and Attenuates Inflammation in Colon of DSS-Treated Piglets.

Inflammatory Bowel Diseases (IBD) are chronic inflammations associated with progressive degradation of intestinal epithelium and impairment of the local innate immune response. Restoring of epithelial integrity and of the mucosal barrier function, together with modulation of inflammatory and innate immune markers, represent targets for alternative strategies in IBD. The aim of our study was to evaluate the effects of a diet including 8% grape seed meal (GSM), rich in bioactive compounds (polyphenols, polyunsaturated fatty acids (PUFAs), fiber) on the markers of colonic epithelial integrity, mucosal barrier function, pro-inflammatory, and innate immunity in DSS-treated piglets used as animal models of intestinal inflammation. Our results have demonstrated the beneficial effects of bioactive compounds from dietary GSM, exerted at three complementary levels: (a) restoration of the epithelial integrity and mucosal barrier reinforcement by modulation of claudins, Occludin (OCCL) and Zonula-1 (ZO-1) tight junction genes and proteins, myosin IXB (MYO9B) and protein tyrosine phosphatase (PTPN) tight junction regulators and mucin-2 (MUC2) gene; (b) reduction of pro-inflammatory MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) genes and activities; and (c) suppression of the innate immune TLR-2 (Toll-like receptor-2) and TLR-4 (Toll-like receptor-4) genes and attenuation of the expression of MyD88 (Myeloid Differentiation Primary Response 88)/MD-2 (Myeloid differentiation factor-2) signaling molecules. These beneficial effects of GSM could further attenuate the transition of chronic colitis to carcinogenesis, by modulating the in-depth signaling mediators belonging to the Wnt pathway.