Innate Immune Inflammation Research Articles

Expression of most retrotransposons in human blood correlates with biological aging.

Retrotransposons (RTEs) have been postulated to reactivate with age and contribute to aging through activated innate immune response and inflammation. Here, we analyzed the relationship between RTE expression and aging using published transcriptomic and methylomic datasets of human blood. Despite no observed correlation between RTE activity and chronological age, the expression of most RTE classes and families except short interspersed nuclear elements (SINEs) correlated with biological age-associated gene signature scores. Strikingly, we found that the expression of SINEs was linked to upregulated DNA repair pathways in multiple cohorts. We also observed DNA hypomethylation with aging and the significant increase in RTE expression level in hypomethylated RTEs except for SINEs. Additionally, our single-cell transcriptomic analysis suggested a role for plasma cells in aging mediated by RTEs. Altogether, our multi-omics analysis of large human cohorts highlights the role of RTEs in biological aging and suggests possible mechanisms and cell populations for future investigations.

Key role for inflammation-related signaling in the pathogenesis of myopia based on evidence from proteomics analysis

The mechanisms underlying myopia pathogenesis are not well understood. Using publicly-available human and animal datasets, we expound on the roles of known, implicated proteins, and new myopia-related signaling pathways were hypothesized. Proteins identified from human serum or ocular fluids, and from ocular tissues in myopic animal models, were uploaded and analyzed with the QIAGEN Ingenuity Pathway Analysis (IPA) software (March 2023). With each IPA database update, more potentially-relevant proteins and signaling pathways previously unavailable during data acquisition are added, allowing extraction of novel conclusions from existing data. Canonical pathway analysis was used to analyze these data and calculate an IPA activation z-score—which indicates not only whether an association is significant, but also whether the pathway is likely activated or inhibited. Cellular immune response and cytokine signaling were frequently found to be affected in both human and animal myopia studies. Analysis of two publicly-available proteomic datasets highlighted a potential role of the innate immune system and inflammation in myopia development, detailing specific signaling pathways involved such as Granzyme A (GzmA) and S100 family signaling in the retina, and activation of myofibroblast trans-differentiation in the sclera. This perspective in myopia research may facilitate development of more effective and targeted therapeutic agents.

Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.

Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease. We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development. Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45hi infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45low microglia and F4/80 + CD45hi infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice. These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.

Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling.

Chronic inflammation contributes to the progression of isoproterenol (ISO)-induced heart failure (HF). Caspase-associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO-driven cardiac remodelling is little explored. This study utilized Card9-/- mice and reconstituted C57BL/6 mice with either Card9-/- or Otud1-/- marrow-derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK-293T cells. Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole-body CARD9 knockout or myeloid-specific CARD9 deletion inhibited ISO-driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO-induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33-linked ubiquitin from CARD9 to promote the assembly of the CARD9-BCL10-MALT1 (CBM) complex, without affecting CARD9 stability. The ISO-activated CBM complex results in NF-κB activation and macrophage-based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid-specific OTUD1 deletion also attenuated ISO-induced murine cardiac inflammation and remodelling. These results suggested that the OTUD1-CARD9 axis is a new pro-inflammatory signal in ISO-challenged macrophages and targeting this axis has a protective effect against ISO-induced HF. Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration. Either whole-body CARD9 knockout or myeloid-specific CARD9 deficiency protected mice from ISO-induced inflammatory heart remodeling. ISO promoted the assembly of CBM complex and then activated NF-κB signaling in macrophages through OTUD1-mediated deubiquitinating modification. OTUD1 deletion in myeloid cells protected hearts from ISO-induced injuries in mice.

Exposure to bacterial PAMPs before RSV infection exacerbates innate inflammation and disease via IL-1α and TNF-α

Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections. Understanding why some individuals get more serious disease may help with diagnosis and treatment. One possible risk factor underlying severe disease is bacterial exposure before RSV infection. Bacterial exposure has been associated with increased respiratory viral-induced disease severity but the mechanism remains unknown. Respiratory bacterial infections or exposure to their pathogen associated molecular patterns (PAMPs) trigger innate immune inflammation, characterised by neutrophil and inflammatory monocyte recruitment and the production of inflammatory cytokines. We hypothesise that these changes to the lung environment alter the immune response and disease severity during subsequent RSV infection. To test this, we intranasally exposed mice to LPS, LTA or Acinetobacter baumannii (an airway bacterial pathogen) before RSV infection and observed an early induction of disease, measured by weight loss, at days 1–3 after infection. Neutrophils or inflammatory monocytes were not responsible for driving this exacerbated weight loss. Instead, exacerbated disease was associated with increased IL-1α and TNF-α, which orchestrated the recruitment of innate immune cells into the lung. This study shows that exposure to bacterial PAMPs prior to RSV infection increases the expression of IL-1α and TNF-α, which dysregulate the immune response resulting in exacerbated disease.

CLADIN- CLADribine and INnate immune response in multiple sclerosis – A phase IV prospective study

Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ ‘non-classical’ monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.

Neutrophil-to-Lymphocyte Ratio, ESR, and CRP Have No Roles as Markers for Disease Severity and Prognosis in Patients with RRMS.

Up to now, there is no definitive prognostic factor for patients with multiple sclerosis. This study aimed to evaluate the neutrophil-to-lymphocyte ratio (N/L ratio) as a cheap, available, and noninvasive marker for disease activity and prognosis. A total of 112 patients, who were diagnosed with relapsing-remitting multiple sclerosis (RRMS), and 61 healthy controls were considered. We evaluated N/L ratio, ESR, CRP in the control, and patients in the first attack of the onset of the disease, 1 month and 6 months later during remission. All patients received interferon or Glatiramer acetate as disease-modifying therapies. The correlation of parameters with Expanded Disability Scale Score (EDSS) and Functional System (FS) involvement was evaluated. The N/L ratio was increased significantly in patients with MS in the relapse phase (mean: 2.44 ± 0.68) compared to the healthy controls (mean: 1.84 ± 0.67) (P = 0.04). Also, we found a significant increase in CRP among the aforementioned groups (P = 0.028). A significant correlation was not found between NLR, ESR, or CRP and patient's EDSS during 6 months of follow-up. For ESR and the type of functional system, a significant difference was found between favorable and unfavorable categories, while the median (IQR) of ESR in the favorable group was 7.7 (4-12) and among unfavorable ones was 13.8 (6-17.75) (P = 0.008). The results showed the effect of the innate immune system and inflammation during MS attacks. We considered that neutrophils, ESR, and CRP cannot predict disease severity or prognosis at least without a combination of other biomarkers.

Sex differences in Huntington's disease from a neuroinflammation perspective.

Huntington's disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune dysregulation, prominently featuring increased immune activity, plays a significant role in HD pathogenesis. In addition to the central nervous system (CNS), systemic innate immune activation and inflammation are observed in HD patients, exacerbating the effects of the Huntingtin (HTT) gene mutation. Recent attention to sex differences in HD symptom severity underscores the need to consider gender as a biological variable in neurodegenerative disease research. Understanding sex-specific immune responses holds promise for elucidating HD pathophysiology and informing targeted treatment strategies to mitigate cognitive and functional decline. This perspective will highlight the importance of investigating gender influence in HD, particularly focusing on sex-specific immune responses predisposing individuals to disease.

Gut Microbiota and Sinusoidal Vasoregulation in MASLD: A Portal Perspective.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition with heterogeneous outcomes difficult to predict at the individual level. Feared complications of advanced MASLD are linked to clinically significant portal hypertension and are initiated by functional and mechanical changes in the unique sinusoidal capillary network of the liver. Early sinusoidal vasoregulatory changes in MASLD lead to increased intrahepatic vascular resistance and represent the beginning of portal hypertension. In addition, the composition and function of gut microbiota in MASLD are distinctly different from the healthy state, and multiple lines of evidence demonstrate the association of dysbiosis with these vasoregulatory changes. The gut microbiota is involved in the biotransformation of nutrients, production of de novo metabolites, release of microbial structural components, and impairment of the intestinal barrier with impact on innate immune responses, metabolism, inflammation, fibrosis, and vasoregulation in the liver and beyond. The gut-liver axis is a conceptual framework in which portal circulation is the primary connection between gut microbiota and the liver. Accordingly, biochemical and hemodynamic attributes of portal circulation may hold the key to better understanding and predicting disease progression in MASLD. However, many specific details remain hidden due to limited access to the portal circulation, indicating a major unmet need for the development of innovative diagnostic tools to analyze portal metabolites and explore their effect on health and disease. We also need to safely and reliably monitor portal hemodynamics with the goal of providing preventive and curative interventions in all stages of MASLD. Here, we review recent advances that link portal metabolomics to altered sinusoidal vasoregulation and may allow for new insights into the development of portal hypertension in MASLD.

Targeted transcriptomic analysis of synovial tissues from horses with septic arthritis treated with immune-activated mesenchymal stromal cells reveals induction of T-cell response pathways.

To investigate mechanistically the reported beneficial effects of immune-activated mesenchymal stromal cell (MSC) therapy to treat equine septic arthritis, leveraging Nanostring technology. 8 Quarter Horses with induced tibiotarsal Staphylococcus aureus septic arthritis treated IA with either Toll-like receptor-3 agonist polyinosinic:polycytidylic acid-activated MSCs + vancomycin antimicrobials (TLR-MSC-VAN; n = 4) or antimicrobials (VAN; 4). Synovial tissues were collected and fixed in neutral-buffered 10% formalin, and formalin-fixed paraffin-embedded synovial and osteochondral tissues were sequenced using a custom-designed 200-gene equine Nanostring nCounter immune panel to directly quantify expression of key immune and cartilage-related genes. Immunohistochemistry to detect CD3+ T cells was performed on synovial tissues to further quantify T-cell infiltration in TLR-MSC-VAN- versus VAN-treated joints. Comparison of synovial transcriptomes between groups revealed moderate changes in differential gene expression, with upregulated expression of 9 genes and downregulated expression of 17 genes with fold change ≥ 2 or ≤ -2 and a significant false discovery rate-adjusted P value of ≤ .05. The most upregulated genes in TLR-MSC-VAN-treated horses included those related to T-lymphocyte recruitment and function, while pathways related to innate immune activation and inflammation were significantly downregulated. Immunohistochemistry and quantitation of CD3+ T-cell infiltrates revealed a numerically greater infiltrate in synovial tissues of TLR-MSC-VAN-treated horses, which did not reach statistical significance in this small sample set (P = .20). Targeted transcriptomic analyses using an equine Nanostring immune and cartilage health panel provided new mechanistic insights into how innate and adaptive immune cells within synovial tissues respond to TLR-activated MSC treatment when used to treat septic arthritis.

The role of γδT lymphocytes in atherosclerosis.

Atherosclerosis poses a significant threat to human health, impacting overall well-being and imposing substantial financial burdens. Current treatment strategies mainly focus on managing low-density lipids (LDL) and optimizing liver functions. However, it's crucial to recognize that Atherosclerosis involves more than just lipid accumulation; it entails a complex interplay of immune responses. Research highlights the pivotal role of lipid-laden macrophages in the formation of atherosclerotic plaques. These macrophages attract lymphocytes like CD4 and CD8 to the inflamed site, potentially intensifying the inflammatory response. γδ T lymphocytes, with their diverse functions in innate and adaptive immune responses, pathogen defense, antigen presentation, and inflammation regulation, have been implicated in the early stages of Atherosclerosis. However, our understanding of the roles of γδ T cells in Atherosclerosis remains limited. This mini-review aims to shed light on the characteristics and functions of γδ T cells in Atherosclerosis. By gaining insights into the roles of γδ T cells, we may uncover a promising strategy to mitigate plaque buildup and dampen the inflammatory response, thereby opening new avenues for effectively managing this condition.

Effect of curcumin on inflammatory and oxidative stress markers in Lipopolysaccharide induced animal models of pre-eclampsia

Introduction: A substantial percentage of fetal, maternal, and neonatal morbidity and mortality is traced to Pre-eclampsia, a life threatening disease. Typical symptoms of the disease include de novo hypertension, proteinuria, renal failure, neurological problems, elevated liver enzymes, and uteroplacental dysfunction. It is estimated that almost 8-10% of all pregnancies are affected by preeclampsia in India. Pre-eclampsia incidentally also involves immune system changes on similar lines as a typical pregnancy. Immune cells like CD4+ T-helper 1 (TH1) cells, cytotoxic NK cells, and autoreactive B cells secrete substances that cause an increase in innate immune activation and inflammation in the maternal circulation and uteroplacental unit, instead of immune changes that promote tolerance and inhibit reactivity to the fetus and placenta. Placental and systemic oxidative stress are the key factors in the emergence of preeclampsia. A number of physiological changes, mineral shortages, and increased oxygen use during pregnancy can all be considered potential causes of oxidative stress. There is yet no effective and secure pharmaceutical treatment for preeclampsia. Pregnancy related safety concerns and the complex aetiology are two significant barriers to the development of pre-eclampsia medications. Medicinal plants and derived products have long been recognized as valuable assets in the treatment of a variety of diseases. Curcumin is a naturally occurring substance with significant in vitro therapeutic promise. The objective of this study was to develop LPS (lipopolysaccharide) induced animal model of Pre-eclampsia and to estimate and compare the hemodynamic parameters, inflammatory markers, oxidative stress markers and proteinuria in pregnant control, LPS-induced Pre-eclampsia, and curcumin-treated Pre-eclampsia in experimental rats. Material and methods: Pre-eclampsia was induced by single dose of 0.5μg/kg LPS. Wistar rats were divided into 8 groups of 8 animals. Female wistar rats were placed with male rats overnight and examined the next morning for the presence of sperm in vaginal smears. The day on which sperm was detected was designated as gestational day 0. After confirmation of pregnancy, each rat was weighed and randomized into groups. Pregnant Wistar rats were given 0.5 μg /kg of body weight LPS intraperitoneally on gestational day 5 for developing Pre-eclampsia models. Protein estimation in urine was done after 24 hours. On 19th or 20th gestation day animals were anesthetized and blood pressure was measured through a non-invasive tail-cuff method using the AD instrument and also through invasive method by inserting a arterial catheter in either of the carotid arteries towards the heart. ECG recording was done through surface ECG recording. Blood was collected by cardiac puncture, centrifuged, and stored at -80ºC on 19th or 20th gestation day. Inflammatory markers were estimated through ELISA reader. Oxidative stress markers were estimated. Pregnancy outcome was assessed through placental weight, number of pup’s delivered and pup’s weight. Statistical analysis was done using one way analysis of variance (ANOVA) followed by post hoc Tukey‘s test for intergroup comparisons. Results: In LPS induced model of pre-eclampsia, single-dose treatment with LPS (0.5ug/kg) induced marked pre-eclampsia in rats. Treatment with curcumin significantly decreased the level of proteinuria, hemodynamic parameters, inflammatory markers and oxidative stress markers in pregnant LPS+ curcumin-treated group when compared with the pregnant LPS group. Treatment with curcumin significantly increases pup’s weight and number of pups. Conclusion: On the basis of this experimental study, it is proposed that curcumin appears to be a potential therapeutic agent as measured by effect on hemodynamic changes, proteinuria, inflammatory markers, oxidative stress markers and pregnancy outcomes in LPS-induced pre- eclampsia. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

An Exploration of Some Predictors of Quality of Life-Related to the Innate Immune System, Inflammation, and Disease Activity in Patients with Behcet's Syndrome: An Analytical Cross-sectional Study.

Behçet's disease (BD) has a growing prevalence in Silk Road countries. The aim of our cross-sectional study was to explore the clinical and molecular predictors of quality of life in BD patients. One hundred and fifty consecutive Iranian BD patients with an age range between 20-50 years were included. The Leeds Behçet's disease quality of life (BDQoL) in Persian form was fulfilled to evaluate the quality of life. Anthropometric measurements were carried out using the calibrated scales. Iranian Behcet's Disease Dynamic Activity Measure (IBDDAM), Behcet's disease current activity form (BDCAF), and Total Inflammatory Activity Index (TIAI) were used to assess BD activity. mRNA expression of toll-like receptors 2 and 4 (TLR2 and TLR4) and tumor-necrosis-factor-alpha (TNF-α) levels in serum were measured by real-time polymerase chain reaction (PCR) and ELISA, respectively. Multiple linear backward regression at P = 0.1 was used to study the potential predictors of quality of life. TLR2 and BDCAF were shown to be the most important predictors of quality of life in BD patients by 22%. There were positive associations between them (β = 0.326, p = 0.013 for BDCAF; β = 0.366, p = 0.006 for TLR2) and BDQoL value. Higher TLR2 expression as a key protein in recognizing pathogens by innate immunity and BDCAF value as a comprehensive BD assessing scale contribute to poor quality of life among BD patients. Emphasizing therapeutically, approaches associated with lower TLR2 expression and BDCAF value can be considered in future studies.

N4BP1 functions as a dimerization-dependent linear ubiquitin reader which regulates TNF signalling

Signalling through TNFR1 modulates proinflammatory gene transcription and programmed cell death, and its impairment causes autoimmune diseases and cancer. NEDD4-binding protein 1 (N4BP1) is a critical suppressor of proinflammatory cytokine production that acts as a regulator of innate immune signalling and inflammation. However, our current understanding about the molecular properties that enable N4BP1 to exert its suppressive potential remain limited. Here, we show that N4BP1 is a novel linear ubiquitin reader that negatively regulates NFκB signalling by its unique dimerization-dependent ubiquitin-binding module that we named LUBIN. Dimeric N4BP1 strategically positions two non-selective ubiquitin-binding domains to ensure preferential recognition of linear ubiquitin. Under proinflammatory conditions, N4BP1 is recruited to the nascent TNFR1 signalling complex, where it regulates duration of proinflammatory signalling in LUBIN-dependent manner. N4BP1 deficiency accelerates TNFα-induced cell death by increasing complex II assembly. Under proapoptotic conditions, caspase-8 mediates proteolytic processing of N4BP1, resulting in rapid degradation of N4BP1 by the 26 S proteasome, and acceleration of apoptosis. In summary, our findings demonstrate that N4BP1 dimerization creates a novel type of ubiquitin reader that selectively recognises linear ubiquitin which enables the timely and coordinated regulation of TNFR1-mediated inflammation and cell death.

Innate Immune Response-Mediated Inflammation in Viral Pneumonia

Abstract Objective This study aims to investigate the intricate interactions between viral infections, specifically within the context of community-acquired pneumonia. We seek to shed light on the underestimation of viral pneumonia cases, utilizing advancements in molecular diagnostic testing. Methods The investigation involves a comprehensive review of existing literature to explore the prevalence and impact of various viruses causing pneumonia in both children and adults. Our focus spans parainfluenza virus, respiratory syncytial virus, human bocavirus, human metapneumovirus, and rhinoviruses in children and coronaviruses, rhinoviruses, and influenza viruses in adults. The study further delves into the host's innate immune response, emphasizing the roles of pattern recognition receptors (PRRs), type I interferons (IFNs), proinflammatory cytokines, and other immune cells during viral infections. Results The analysis reveals a substantial global burden of viral community-acquired pneumonia, estimating approximately 200 million cases annually in children and adults combined. This study underscores viruses' significant, previously underestimated role in causing pneumonia. Insights into specific viruses affecting different age groups and their prevalence in various geographical settings are provided. Conclusion In conclusion, this review emphasizes the necessity of recognizing the substantial contribution of viral infections to community-acquired pneumonia cases. The host's innate immune response, mediated by PRRs, type I IFNs, and other immune mediators, is pivotal in preventing viral invasion and replication. The study accentuates the importance of continued research into understanding the innate immune mechanisms involved in viral infections and the resulting inflammation.

Dysregulation of iron transport-related biomarkers in blood leukocytes is associated with poor prognosis of early trauma

ObjectiveThe early targeted and effective diagnosis and treatment of severe trauma are crucial for patients' outcomes. Blood leukocytes act as significant effectors during the initial inflammation and activation of innate immunity in trauma. This study aims to identify hub genes related to patients' prognosis in blood leukocytes at the early stages of trauma. MethodsThe expression profiles of Gene Expression Omnibus (GEO) Series (GSE) 36809 and GSE11375 were downloaded from the GEO database. R software, GraphPad Prism 9.3.1 software, STRING database, and Cytoscape software were used to process the data and identify hub genes in blood leukocytes of early trauma. ResultsGene Ontology (GO) analysis showed that the differentially expressed genes (DEGs) of blood leukocytes at the early stages of trauma (0–4 h, 4–8 h, and 8–12 h) were mainly involved in neutrophil activation and neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity, lymphocyte differentiation, and cell killing. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs were mainly involved in Osteoclast differentiation and Hematopoietic cell lineage. Sixty-six down-regulated DEGs and 148 up-regulated DEGs were identified and 37 hub genes were confirmed by Molecular Complex Detection (MCODE) of Cytoscape. Among the hub genes, Lipocalin 2 (LCN2), Lactotransferrin (LTF), Olfactomedin 4 (OLFM4), Resistin (RETN), and Transcobalamin 1 (TCN1) were related to prognosis and connected with iron transport closely. LCN2 and LTF were involved in iron transport and had a moderate predictive value for the poor prognosis of trauma patients, and the AUC of LCN2 and LTF was 0.7777 and 0.7843, respectively. ConclusionAs iron transport-related hub genes in blood leukocytes, LCN2 and LTF can be used for prognostic prediction of early trauma.

Increased cardiovascular risk in patients with chronic kidney disease.

Cardiovascular disease (CVD) is highly prevalent in patients suffering from chronic kidney disease (CKD). The risk of patients with CKD developing CVD is manifested already in the early stages of CKD development. The impact of declined kidney function on increased cardiovascular risk and the underlying mechanisms are complex and multifactorial. This review discusses the impact of (a) traditional cardiovascular risk factors such as smoking, dyslipidemia, diabetes, and hypertension as well as (b) CKD-specific pathophysiological and molecular mechanisms associated with an increased cardiovascular risk. The latter include uremic toxins, post-translational modifications and uremic lipids, innate immune cell activation and inflammation, oxidative stress, endothelial cell dysfunction, increased coagulation and altered platelet responses, vascular calcification, renin-angiotensin-aldosterone-system (RAAS) and sympathetic activation, as well as anemia. Unraveling the complex interplay of different risk factors, especially in the context of patient subcohorts, will help to find new therapeutic approaches in order to reduce the increased cardiovascular risk in this vulnerable patient cohort.

Innate immune responsive inflammation in development of progressive myopia.

Inflammation has been implicated for development of myopia. It is not clear when inflammation is kicked in during the course of myopia, and what characteristics of the inflammation. In this study, we tested for cytokines from aqueous humour of eyes with wide spectrum of refractive status for profiling the inflammation. Aqueous humour of 142 patient eyes were tested for soluble intercellular adhesion molecule 1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta 2 (TGF-β2) using an enzyme-linked immunosorbent assay (ELISA). Eye globe axial length of these patients ranged from emmetropia to high myopia. Of 142 patients, an average axial length is 25.51 ± 3.31 mm, with a range of 21.56-34.37 mm. There are 36 cases in lower 25 percentile, 37 cases in upper 25 percentile, and 69 case in the middle 50 percentile. sICAM-1 and MCP-1 were significantly higher in the eyes with staphyloma (407.48 pg/mL, 312.31 pg/mL, n = 33) or macular schisis (445.86 pg/mL,345.33 pg/mL, n = 19) than that in the eyes without these changes (206.44 pg/mL, 244.76 pg/mL, n = 107). All three cytokines level was significantly associated with eye globe axial in a positive mode while adjusting for the age and sex. Strength of the association was the greatest for sICAM-1 and the weakest for TGF- β2. MCP-1 was in between. sICAM-1 and MCP-1 in ocular fluid may be indicative biomarkers for progressive high myopia and the underneath autoimmune inflammation. sICAM-1 may be used as a monitoring biomarker for development of pathologic myopia.

P108 Response to vedolizumab in ulcerative colitis is associated with reduced neutrophil extracellular traps formation and IL-1β production: insights from NEUTROVED study

Abstract Background Vedolizumab (VDZ) is a humanized mAb against integrin α4β7. VDZ inhibits gut inflammation by impeding intestinal T-cell homing, however, recent data suggest that effects of α4β7 blocking extend beyond T-cells to alterations in innate immunity. Neutrophils are key components of innate immune response and inflammation in ulcerative colitis (UC). Studies have provided evidence linking neutrophils with UC pathogenesis, through autophagy induction and production of IL-1β-enriched neutrophil extracellular traps (NETs). NEUTROVED aimed to investigate the effects of VDZ treatment on neutrophils that may be associated with clinical and endoscopic response. Methods Patients with moderate-to-severe UC who received VDZ in standard medical care were evaluated in two timepoints, 24 hours before treatment initiation (T1) and at week 14 of treatment (T2). Clinical/endoscopic scores and common laboratory indexes were evaluated. In parallel, RNA-sequencing in peripheral neutrophils was performed, and markers of NETs in plasma and intestinal biopsies were assessed. Results In total 5 patients completed the study until today (Table 1). In T2, 4 patients demonstrated complete remission, and one patient had mild disease. No adverse events were recorded. RNA-sequencing analysis of paired samples revealed 248 significantly downregulated and 109 upregulated genes in peripheral neutrophils after VDZ treatment. Bioinformatics analysis using the GeneCodis4 web-based tool revealed that downregulated DEGs clustered mainly in immune-related pathways, including neutrophil degranulation, Toll-like receptor cascades, signaling by interleukins, NETs formation, and HIF-1 signaling pathway, while upregulated DEGs were involved in RNA metabolism-related processes, and the ribosome biogenesis pathway. A comparative analysis between these differentially expressed genes (DEGs) and our previous RNA-sequencing data of peripheral neutrophils isolated from active UC patients (n=24) highlighted a set of 168 DEGs as restored targets after VDZ therapy. Of note, several unique genes implicated in neutrophil activation, including IL-1 signaling components, were found significantly downregulated after VDZ therapy. In line with the abovementioned transcriptome alterations, markers of NETs and IL1β-bearing NETs in plasma and colonic tissue were significantly reduced, recapitalizing clinical and endoscopic response to VDZ. Conclusion Response to VDZ treatment in UC is related to anti-inflammatory actions on neutrophils characterized by reduced NETosis and IL-1β production through NETs. Further mechanistic studies investigating the possible effects of VDZ on innate immunity and neutrophil-mediated responses are warranted.

Mitochondria driven innate immune signaling and inflammation in cancer growth, immune evasion, and therapeutic resistance.

Mitochondria play an important and multifaceted role in cellular function, catering to the cell's energy and biosynthetic requirements. They modulate apoptosis while responding to diverse extracellular and intracellular stresses including reactive oxygen species (ROS), nutrient and oxygen scarcity, endoplasmic reticulum stress, and signaling via surface death receptors. Integral components of mitochondria, such as mitochondrial DNA (mtDNA), mitochondrial RNA (mtRNA), Adenosine triphosphate (ATP), cardiolipin, and formyl peptides serve as major damage-associated molecular patterns (DAMPs). These molecules activate multiple innate immune pathways both in the cytosol [such as Retionoic Acid-Inducible Gene-1 (RIG-1) and Cyclic GMP-AMP Synthase (cGAS)] and on the cell surface [including Toll-like receptors (TLRs)]. This activation cascade leads to the release of various cytokines, chemokines, interferons, and other inflammatory molecules and oxidative species. The innate immune pathways further induce chronic inflammation in the tumor microenvironment which either promotes survival and proliferation or promotes epithelial to mesenchymal transition (EMT), metastasis and therapeutic resistance in the cancer cell's. Chronic activation of innate inflammatory pathways in tumors also drives immunosuppressive checkpoint expression in the cancer cells and boosts the influx of immune-suppressive populations like Myeloid-Derived Suppressor Cells (MDSCs) and Regulatory T cells (Tregs) in cancer. Thus, sensing of cellular stress by the mitochondria may lead to enhanced tumor growth. In addition to that, the tumor microenvironment also becomes a source of immunosuppressive cytokines. These cytokines exert a debilitating effect on the functioning of immune effector cells, and thus foster immune tolerance and facilitate immune evasion. Here we describe how alteration of the mitochondrial homeostasis and cellular stress drives innate inflammatory pathways in the tumor microenvironment.