Identification of neutrophil extracellular traps genes as potential biomarkers in psoriasis based on bioinformatics analysis.

The epidermal infiltration of neutrophils is a hallmark of psoriasis (PSO) and its activation leads to the release of neutrophil extracellular traps (NETs). However, the molecular mechanism of NETs-related genes (NETRGs) has not been extensively studied in PSO. To define NETs-related-biomarkers for PSO. The GSE13355 and GSE78097 datasets, and NETRGs gene set were included in this study. The datasets used in this study were all microarray data. The weighted gene co-expression network analysis (WGCNA) and machine learning algorithms were used to mine key genes. Later on, single-gene gene set enrichment analysis (GSEA) and immune infiltration analysis were implemented. Finally, the expression of key genes was verified using quantitative real-time fluorescence PCR (qRT-PCR). A total of 3 key genes (S100A9, CLEC7A, and CXCR4) were derived, and they all had excellent diagnostic performance. The single-gene GSEA enrichment results indicated that the key genes were mainly enriched in the chemokine signaling pathway and humoral immune response in the high-expression group, while focal adhesion was enriched in the low-expression group. The correlation analysis indicated that all key genes were strongly negatively correlated with resting mast cells and TGF-ß family member receptor, while they were strongly positively correlated with activated CD4 memory T cells and antigen processing and presentation. Lastly, the experimental results showed that the expression trends of key genes were consistent with public database. In this study, we successfully screened three potential PSO diagnostic genes (S100A9, CLEC7A and CXCR4) that were closely related to NETs, and these findings not only provided new molecular marker candidates for the precise diagnosis of PSO patients, but also revealed possible future therapeutic targets. However, further in-depth research and validation were necessary.

Postnatal supplementation with alarmins S100a8/a9 ameliorates malnutrition-induced neonate enteropathy in mice.

Malnutrition is linked to 45% of global childhood mortality, however, the impact of maternal malnutrition on the child's health remains elusive. Previous studies suggested that maternal malnutrition does not affect breast milk composition. Yet, malnourished children often develop a so-called environmental enteropathy, assumed to be triggered by frequent pathogen uptake and unfavorable gut colonization. Here, we show in a murine model that maternal malnutrition induces a persistent inflammatory gut dysfunction in the offspring that establishes during nursing and does not recover after weaning onto standard diet. Early intestinal influx of neutrophils, impaired postnatal development of gut-regulatory functions, and expansion of Enterobacteriaceae were hallmarks of this enteropathy. This gut phenotype resembled those developing under deficient S100a8/a9-supply via breast milk, which is a known key factor for the postnatal development of gut homeostasis. We could confirm that S100a8/a9 is lacking in the breast milk of malnourished mothers and the offspring's intestine. Nutritional supply of S100a8 to neonates of malnourished mothers abrogated the aberrant development of gut mucosal immunity and microbiota colonization and protected them lifelong against severe enteric infections and non-infectious bowel diseases. S100a8 supplementation after birth might be a promising measure to counteract deleterious imprinting of gut immunity by maternal malnutrition.

The role of the S100A8/S100A9 in gastric tumor progression.

Gastric premalignant lesions can develop into cancer through multiple steps and inflammation plays a critical role. The aim of this study is to uncover the characteristics of macrophages and their gene expression in premalignant gastric lesions to identify novel biomarkers and potential targets for treatment. We used the computational algorithm CIBERSORT to estimate immune cell subsets present in gastric tissue. We applied WGCNA to identify inflammation-related modules and hub genes. Single-cell analysis was used to identify macrophage sub-clusters specific to pathology. In addition, the in-vitro experiment was performed to verify the mechanism of the key inflammatory factors in the growth of gastric cancer. WGCNA identified a module that was positively correlated with pathological changes and highly related to inflammation scores. Single-cell analysis revealed a macrophage subset, and we observed that S100A8 and S100A9 + macrophages made up a significantly higher proportion in early gastric cancer (EGC) tissues. Our functional enrichment analysis suggested that these macrophages may play a role in gastric tumorigenesis through the activation of the NFκB signaling pathway. In vitro experiments verified that S100A9 can promote the proliferation and migration of AGS cells through the TLR4-NFκB signaling pathway, and the S100A8/S100A9 inhibitor Paquinimod can inhibit their proliferation and migration. Our findings suggest that S100A8 and S100A9 + macrophages may activate the TLR4-NFκB signaling pathway to promote cell proliferation and migration leading to gastric tumor progression. Macrophages with high expression of S100A8/S100A9 are critical in the progression of gastric inflammation to cancer. Cytokine S100A9 can activate the TLR4-NFκB signaling pathway and promote the proliferation and migration of gastric adenocarcinoma cells.

FPR1 signaling aberrantly regulates S100A8/A9 production by CD14+FCN1hi macrophages and aggravates pulmonary pathology in severe COVID-19.

Excessive alarmins S100A8/A9 escalate the inflammation and even exacerbate immune-driven thrombosis and multi-organ damage. However, the regulatory mechanisms of S100A8/A9 expression in infectious diseases remain unclear. In this study, high-dimensional transcriptomic data analyses revealed a high proportion of CD14+FCN1hi macrophages within the pulmonary niche post-severe SARS-CoV-2 infection. By constructing the S100-coexpression gene list and supervised module scoring, we found that CD14+FCN1hi macrophages presented the highest scores of alarmin S100, and possibly served as the trigger and amplifier of inflammation in severe COVID-19. These CD14+FCN1hi cells lacked the positive regulatory activity of transcription factor PPARγ, and lost their differentiation ability towards mature macrophages. Ex vivo experiments further validated that the epithelial cells with high ORF-3a expression promoted the expression and secretion of S100A8/A9 through ANXA1/SAA1-FPR1 signaling. S100A8/A9 heterodimers, as well as the co-localization of S100A8/A9 with microtubules, were both diminished by the FPR1 inhibitor. Phospho-kinase protein array indicated that STAT3 promoted transcription, and PLC-γ and ERK1/2 pathways were involved in the hetero-dimerization and unconventional secretion of S100A8/A9. Our study highlights the pivotal role of FPR1 signaling in the excessive production of S100A8/A9 and provides a promising target for the prevention and control of severe COVID-19 and post-acute COVID-19 sequelae.

Dysregulated S100A9 Expression Impairs Matrix Deposition in Chronic Wounds.

Chronic non-healing wounds are characterized by persistent inflammation, excessive matrix-degrading proteolytic activity and compromised extracellular matrix (ECM) synthesis. Previous studies showed that S100A8/A9 are strongly dysregulated in delayed wound healing and impair the proper function of immune cells. Here, we demonstrate an unrecognized pathological function of S100A9 overexpression in wounds with impaired healing that directly affects ECM functions in fibroblasts. S100A9 was analyzed in two different mouse models mimicking the features of the two most prominent types of non-healing wounds in humans. Db/db mice were used as a model for diabetes-associated impaired wound healing. Iron-overloaded mice were used to mimic the conditions of impaired wound healing in chronic venous leg ulcers. The skin wounds of both mouse models are characterized by delayed wound closure, high and sustained expression of pro-inflammatory mediators and a substantially decreased ECM deposition, all together the hallmarks of non-healing wounds in humans. The wounds of both mouse models also present a solid and prolonged expression of S100A8 and S100A9 that coincides with a compromised ECM deposition and that was confirmed in chronic wounds in humans. Mechanistically, we reveal that S100A9 directly affects ECM deposition by shifting the balance of expression of ECM proteins and ECM degrading enzymes in fibroblasts via toll-like-receptor 4-dependent signaling. Consequently, blocking S100A9 during delayed wound healing in db/db mice restores fibroblast ECM functions eliciting increased matrix deposition. Our data indicate that the dysregulation of S100A9 directly contributes to a compromised ECM deposition in chronic wounds and further suggests S100A9 as a promising therapeutic target to improve tissue repair in chronic wounds.

Acute blood loss in mice forces differentiation of both CD45-positive and CD45-negative erythroid cells and leads to a decreased CCL3 chemokine production by bone marrow erythroid cells.

Hemorrhage, a condition that accompanies most physical trauma cases, remains an important field of study, a field that has been extensively studied in the immunological context for myeloid and lymphoid cells, but not as much for erythroid cells. In this study, we studied the immunological response of murine erythroid cells to acute blood loss using flow cytometry, NanoString immune transcriptome profiling, and BioPlex cytokine secretome profiling. We observed that acute blood loss forces the differentiation of murine erythroid cells in both bone marrow and spleen and that there was an up-regulation of several immune response genes, in particular pathogen-associated molecular pattern sensing gene Clec5a in post-acute blood loss murine bone marrow erythroid cells. We believe that the up-regulation of the Clec5a gene in bone marrow erythroid cells could help bone marrow erythroid cells detect and eliminate pathogens with the help of reactive oxygen species and antimicrobial proteins calprotectin and cathelicidin, the genes of which (S100a8, S100a9, and Camp) dominate the expression in bone marrow erythroid cells of mice.

Netrin-1-CD146 and netrin-1-S100A9 are associated with early stage of lymph node metastasis in colorectal cancer.

BACKGROUND: The netrin-1/CD146 pathway regulates colorectal cancer (CRC) liver metastasis, angiogenesis, and vascular development. However, few investigations have yet examined the biological function of netrin-1/CD146 complex in CRC. In this work, we investigated the relationship between the netrin-1/CD146 axis and S100 proteins in sentinel lymph node, and revealed a possible new clue for vascular metastasis of CRC. METHODS: The expression levels of netrin-1 and CD146 proteins in CRC, as well as S100A8 and S100A9 proteins in the sentinel lymph nodes were determined by immunohistochemistry. Using GEPIA and UALCAN, we analyzed netrin-1 and CD146 gene expression in CRC, their association with CRC stage, and their expression levels and prognosis in CRC patients. RESULTS: The expression level of netrin-1 in N1a+1b (CRC lymphatic metastasis groups, exculded N1c) was positively increased with N0 (p = 0.012). The level of netrin-1 protein was positively correlated with CD146 protein (p < 0.05). The level of S100A9 protein was positively correlated with CD146 protein (r = 0.492, p = 0.007). Moreover, netrin-1 expression was obviously correlated with S100A9 expression in the N1 stage (r = 0.867, p = 0.000). CD146 level was correlated with S100A9 level in the N2 stage (r = 0.731, p = 0.039). CD146 mRNA expression was higher in normal colorectal tissues than in CRC (p < 0.05). Netrin-1 and CD146 expression were not significantly associated with the tumor stages and prognosis of patients with CRC (p > 0.05). CONCLUSIONS: The netrin-1/CD146 and netrin-1/S100A9 axis in CRC tissues might related with early stage of lymph node metastasis, thus providing potential novel channels for blocking lymphatic metastasis and guiding biomarker discovery in CRC patients.

S100A9, as a potential predictor of prognosis and immunotherapy response for GBM, promotes the malignant progression of GBM cells and migration of M2 macrophages.

In the past decades, the therapeutic effect of glioblastoma (GBM) has not been significantly improved. Generous evidence indicates that S100A9 has a wide range of functions in tumors, but its exploration in GBM is less. The purpose of this study is to conduct a comprehensive bioinformatics analysis and cytological experiment on S100A9 in GBM. The expression data and clinical data of GBM samples were downloaded from the public database, and comprehensive bioinformatics analysis was performed on S100A9 in GBM using R software. Wound healing assay and transwell assay were used to detect the migration activity of cells, and colony formation assay, EdU staining, and CCK-8 assay were used to detect the proliferation activity of cells. The effect of S100A9 on the migration activity of M2 macrophages was verified by the cell co-culture method. The protein expression was detected by western blotting and immunohistochemical staining. S100A9 is an independent prognostic factor in GBM patients and is related to poor prognosis. It can be used as an effective tool to predict the response of GBM patients to immune checkpoint inhibitors (ICIs). In addition, S100A9 can promote the malignant progression of GBM and the migration of M2 macrophages. On the whole, our study highlights the potential value of S100A9 in predicting prognosis and immunotherapeutic response in GBM patients. More importantly, S100A9 may promote the malignant progress of GBM by involving in some carcinogenic pathways and remodeling the tumor microenvironment (TME).

S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke.

BACKGROUND: Microglia and infiltrated macrophages (M/M) are integral components of the innate immune system that play a critical role in facilitating brain repair after ischemic stroke (IS) by clearing cell debris. Novel therapeutic strategies for IS therapy involve modulating M/M phenotype shifting. This study aims to elucidate the pivotal role of S100A9 in M/M and its downstream STAT6/PPARγ signaling pathway in neuroinflammation and phagocytosis after IS. METHODS: In the clinical study, we initially detected the expression pattern of S100A9 in monocytes from patients with acute IS and investigated its association with the long-term prognosis. In the in vivo study, we generated the S100A9 conditional knockout (CKO) mice and compared the stroke outcomes with the control group. We further tested the S100A9-specific inhibitor paqunimod (PQD), for its pharmaceutical effects on stroke outcomes. Transcriptomics and in vitro studies were adopted to explore the mechanism of S100A9 in modulating the M/M phenotype, which involves the regulation of the STAT6/PPARγ signaling pathway. RESULTS: S100A9 was predominantly expressed in classical monocytes and was correlated with unfavorable outcomes in patients of IS. S100A9 CKO mitigated infarction volume and white matter injury, enhanced cerebral blood flow and functional recovery, and prompted anti-inflammation phenotype and efferocytosis after tMCAO. The STAT6/PPARγ pathway, an essential signaling cascade involved in immune response and inflammation, might be the downstream target mediated by S100A9 deletion, as evidenced by the STAT6 phosphorylation inhibitor AS1517499 abolishing the beneficial effect of S100A9 inhibition in tMCAO mice and cell lines. Moreover, S100A9 inhibition by PQD treatment protected against neuronal death in vitro and brain injuries in vivo. CONCLUSION: This study provides evidence for the first time that S100A9 in classical monocytes could potentially be a biomarker for predicting IS prognosis and reveals a novel therapeutic strategy for IS. By demonstrating that S100A9-mediated M/M polarization and phagocytosis can be reversed by S100A9 inhibition in a STAT6/PPARγ pathway-dependent manner, this study opens up new avenues for drug development in the field.

S100A9-TLR4 axis aggravates dry eye through the blockage of autophagy.

This research focused on how upregulation of S100A9 contributed to the pathogenesis of the dry eye disease (DED) and whether S100A9 served as a promising therapeutic target in DED. Public single-cell RNA sequencing (scRNA-seq) data of a lacrimal gland excision (LGE) murine DED model was analyzed. LGE model was established and expression of protein was measured through immunofluorescence and Western blot. DED-related signs were evaluated through tear secretion and fluorescent staining. TUNEL was performed to detect the level of cell death. Briefly, S100A9 was recognized as a highly variable gene in the DED group. LGE model was successfully established, and S100A9 showed a time-dependent increase in the corneal epithelia. Autophagic blockage was predicted by the scRNA-seq data in DED, and further verified by decrease of LC3B-II/LC3B-I and increase of SQSTM1 and p-mTOR/mTOR, while S100A9 inhibitor paquinimod (PAQ) reversed the changes. PAQ also downregulated TLR4, and inhibition of TLR4 also alleviated autophagic blockage in DED. Finally, signs of DED, chronic corneal inflammation and cell death got a remission after either inhibition of S100A9 or TLR4. In general, we deduced a S100A9-TLR4-Autophagic blockage pathway in the pathogenesis of DED.

S100a8/a9 regulated by LPS/TLR4 axis plays an important role in Salmonella-based tumor therapy and host defense.

Bacteria are ideal anticancer agents and carriers due to their unique capabilities that are convenient in genetic manipulation, tumor-specific targeting, and deep-tissue penetration. However, the specific molecular mechanisms of bacteria-mediated cancer therapy (BMCT) have not been clarified. In this study, we found that TLR4 signaling pathway is critical for Salmonella-mediated tumor targeting, tumor suppression, and liver and spleen protection. TLR4 knockout in mice decreased the levels of cytokines and chemokines, such as S100a8, S100a9, TNF-α, and IL-1ß, in tumor microenvironments (TMEs) after Salmonella treatment, which inhibited tumor cell death and nutrient release, led to reduced bacterial contents in tumors and attenuated antitumor efficacy in a negative feedback manner. Importantly, we found that S100a8 and S100a9 played a leading role in Salmonella-mediated cancer therapy (SMCT). The antitumor efficacy was abrogated and liver damage was prominent when blocked with a specific inhibitor. These findings elucidated the mechanism of Salmonella-mediated tumor targeting, suppression, and host antibacterial defense, providing insights into clinical cancer therapeutics.

Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair.

Cardiac mononuclear phagocytic cells (Cardiac MPCs) participate in maintaining homeostasis and orchestrating cardiac responses upon injury. However, the function of specific MPC subtypes and the related cell fate commitment mechanisms remain elusive in regenerative and nonregenerative hearts due to their cellular heterogeneities. Using spatiotemporal single-cell epigenomic analysis of cardiac MPCs in regenerative (P1) and nonregenerative (P10) mouse hearts after injury, we found that P1 hearts accumulate reparative Arg1+ macrophages, while proinflammatory S100a9+Ly6c+ monocytes are uniquely abundant during nonregenerative remodeling. Moreover, blocking chemokine CXCR2 to inhibit the specification of the S100a9+Ly6c+-biased inflammatory fate in P10 hearts resulted in elevated wound repair responses and marked improvements in cardiac function after injury. Single-cell RNA-Seq further confirmed an increased Arg1+ macrophage subpopulation after CXCR2 blockade, which was accomplished by increased expression of wound repair-related genes and reduced expression of proinflammatory genes. Collectively, our findings provide instructive insights into the molecular mechanisms underlying the function and fate specification of heterogeneous MPCs during cardiac repair and identify potential therapeutic targets for myocardial infarction.

TLR2 Derangements Likely Play a Significant Role in the Inflammatory Response and Thrombosis in Patients with Ph(-) Classical Myeloproliferative Neoplasm.

We investigated the role of toll-like receptors (TLRs) in inflammatory pathways in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-)MPNs). TLR2 expression was increased in ET, PV, and MPN (grouped as (PV + (ET) + MF)), whereas TLR4 was elevated only in MPN. TLR3, 7, and 9 were not elevated. Cultured monocyte-derived dendritic cells and plasma assays in TLR2-elevated patients were found to secrete more cytokines than those from TLR2-normal patients. These facts suggest that TLR2 is the major inflammatory pathways in MPN. We also measured S100A9 and reactive oxygen species (ROS), revealing increased S100A9 in PV, MF, and MPN, while ROS were only increased in MF. These data suggests that MPNs initially involve TLR2, with minor contributions from TLR4, and with S100A9, leading to ROS formation, JAK2 mutation, and progression to MF or leukemia. Furthermore, patients with JAK2 mutations or leukocytosis exhibited higher TLR2 expression. In leukocyte-platelet interactions, cells from MPN patients displayed a stronger response to a TLR2 agonist than TLR4 agonist. A TLR2 inhibitor (but not a TLR4 inhibitor) attenuated this response. Thrombosis incidence was higher in TLR2-elevated patients (29%) than in TLR2-normal patients (19%). These findings suggest that TLR2 likely contributes to thrombosis in MPN.

Elucidating the pan-oncologic landscape of S100A9: prognostic and therapeutic corollaries from an integrative bioinformatics and Mendelian randomization analysis.

The calcium-binding protein S100A9 has emerged as a pivotal biomolecular actor in oncology, implicated in numerous malignancies. This comprehensive bioinformatics study transcends traditional boundaries, investigating the prognostic and therapeutic potential of S100A9 across diverse neoplastic entities. Leveraging a wide array of bioinformatics tools and publicly available cancer genomics databases, such as TCGA, we systematically examined the S100A9 gene. Our approach included differential expression analysis, mutational burden assessment, protein interaction networks, and survival analysis. This robust computational framework provided a high-resolution view of S100A9's role in cancer biology. The study meticulously explored S100A9's oncogenic facets, incorporating comprehensive analyses of its relationship with prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, and immune cell infiltration across various tumor types. This study presents a panoramic view of S100A9 expression across a spectrum of human cancers, revealing a heterogeneous expression landscape. Elevated S100A9 expression was detected in malignancies such as BLCA (Bladder Urothelial Carcinoma), CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), COAD (Colon adenocarcinoma), ESCA (Esophageal carcinoma), and GBM (Glioblastoma multiforme), while reduced expression was noted in BRCA (Breast invasive carcinoma), HNSC (Head and Neck squamous cell carcinoma), and KICH (Kidney Chromophobe). This disparate expression pattern suggests that S100A9's role in cancer biology is multifaceted and context-dependent. Prognostically, S100A9 expression correlates variably with patient outcomes across different cancer types. Furthermore, its expression is intricately associated with TMB and MSI in nine cancer types. Detailed examination of six selected tumors-BRCA, CESC, KIRC (Kidney renal clear cell carcinoma), LUSC (Lung squamous cell carcinoma), SKCM (Skin Cutaneous Melanoma); STAD (Stomach adenocarcinoma)-revealed a negative correlation of S100A9 expression with the infiltration of most immune cells, but a positive correlation with neutrophils, M1 macrophages, and activated NK cells, highlighting the complex interplay between S100A9 and the tumor immune environment. This bioinformatics synthesis posits S100A9 as a significant player in cancer progression, offering valuable prognostic insights. The data underscore the utility of S100A9 as a prognostic biomarker and its potential as a therapeutic target. The therapeutic implications are profound, suggesting that modulation of S100A9 activity could significantly impact cancer management strategies.

High-dose vitamin C attenuates radiation-induced pulmonary fibrosis by targeting S100A8 and S100A9.

Radiation-induced pulmonary fibrosis (RIPF) is a frequently encountered late complication in patients undergoing radiation therapy, presenting a substantial risk to patient mortality and quality of life. The pathogenesis of RIPF remains unclear, and current treatment options are limited in efficacy. High-dose vitamin C has demonstrated potential when used in conjunction with other adjuvant therapies due to potent anticancer properties. However, the potential relationship between high-dose vitamin C and RIPF has not yet been explored in existing literature. In our study, the RIPF model and the LLC tumor model were used as two animal models to explore how high-dose vitamin C can improve RIPF without hampering the antitumour efficacy of radiotherapy. The impact of high-dose vitamin C on RIPF was assessed through various assays, including micro-CT, HE staining, Masson staining, and immunohistochemistry. Our results indicated that administering high-dose vitamin C 2 days before radiation and continuing for a duration of 6 weeks significantly inhibited the progression of RIPF. In order to explore the mechanism by which high-dose vitamin C attenuates RIPF, we utilized RNA-seq analysis of mouse lung tissue in conjunction with publicly available databases. Our findings indicated that high-dose vitamin C inhibits the differentiation of fibroblasts into myofibroblasts by targeting S100A8 and S100A9 derived from neutrophils. Additionally, the combination of high-dose vitamin C and radiation demonstrated enhanced inhibition of tumor growth in a murine LLC tumor model. These results revealed that the combination of radiotherapy and high-dose vitamin C may offer a promising therapeutic approach for the clinical management of thoracic tumors and the prevention of RIPF.

Alarming and calming: Dual functions of S100A9 on Mycoplasma gallisepticun infection in avian cells.

Mycoplasma gallisepticum (MG) is the primary causative agent of chronic respiratory disease (CRD) in chickens, characterized by respiratory inflammation. S100A9 plays a pivotal role in modulating the inflammatory response to microbial pathogens. Our prior investigation revealed a significant upregulation of S100A9 in the lungs of chickens following MG infection. This study delves into the immunomodulatory effects of S100A9 during MG infection, demonstrating a notable increase in S100A9 levels in the lungs, immune organs, alveolar epithelial type II cells (AECII), and macrophage HD11 cells of MG-infected chicks and embryos. In MG-infected AECII cells, S100A9 overexpression significantly enhanced MG proliferation and adhesion, suppressed AVBD1, NFκB, pro-inflammatory factors (IL1ß and TNFα), and chemokines, reduced apoptosis, and promoted cell proliferation, thereby facilitating MG infection. Conversely, inhibiting S100A9 produced opposing effects. In MG-infected HD11 cells, S100A9 impeded MG proliferation and adhesion, increased AVBD1, NFκB, pro-inflammatory factors, and chemokines, and induced cell apoptosis while inhibiting proliferation. Additional results demonstrated that S100A9 facilitates MG infection by modulating the TLR7/NFκB/JAK/STAT pathway in AECII/HD11 cells. In summary, S100A9 exhibits a dual role in activating/inhibiting the natural immune response through TLR7/NFκB/JAK/STAT pathway regulation. This dual role promotes MG infection in AECII cells while enabling MG to evade immune surveillance by HD11 cells, ultimately enhancing the overall infection process. These findings advance our understanding of host-pathogen interactions during MG infection and underscore S100A9's potential as a therapeutic target for CRD in chickens.

Neutrophil-secreted S100A8/A9 participates in fatty liver injury and fibrosis by promoting myofibroblast migration.

Fatty liver, which is induced by abnormal lipid metabolism, is one of the most common causes of chronic liver disease globally and causes liver fibrosis. During this process, bone marrow-derived mesenchymal stromal cells (BMSCs) and hepatic stellate cells (HSCs) migrate toward the injured liver and participate in fibrogenesis by transdifferentiating into myofibroblasts. S100A8/A9 is a powerful inducer of cell migration and is involved in liver injury. But there are few reports about the effects of S100A8/A9 on BMSC/HSC migration. In the current study, we found that S100A8/A9 expression was increased during fatty liver injury/fibrogenesis. Moreover, S100A8/A9 expression had a positive correlation with fibrosis marker gene expressions in the injured liver. S100A8/A9 was mainly produced by neutrophils in the fibrotic liver. In vitro, neutrophil-secreted S100A8/A9 promoted BMSC/HSC migration via remodeling of microfilaments. Using specific siRNA and inhibitor, we proved that S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. Moreover, S100A8/A9 knock-down alleviated liver injury and fibrogenesis in vivo, while injection of S100A9 neutralizing antibody performed similar roles. We proved that S100A8/A9 was involved in liver injury and fibrogenesis via inducing BMSC/HSC migration. Our research reveals a new mechanism underlying BMSC/HSC migration in liver fibrosis and suggests S100A8/A9 as a potential therapeutic target of liver fibrosis. KEY MESSAGES: S100A8/A9 is secreted by neutrophils and increased in fatty liver injury. Neutrophil-secreted S100A8/A9 is a mediator of BMSC/HSC migration in vitro. S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. S100A8/A9 blockade alleviates liver injury and fibrogenesis in vivo.

Unraveling shared molecular signatures and potential therapeutic targets linking psoriasis and acute myocardial infarction.

Psoriasis, a chronic inflammatory skin disorder, is associated with comorbidities such as acute myocardial infarction (AMI). However, the molecular mechanisms connecting these conditions are unclear. In this study, we conducted bioinformatics analyses using gene expression datasets to identify differentially expressed genes and hub genes associated with both psoriasis and AMI. Our findings emphasize the involvement of immune-related pathways in the pathogenesis of both conditions. Furthermore, we investigated the expression levels of hub genes in AMI patients and myocardial infarction (MI) mice. ELISA measurements revealed significantly higher levels of CXCL8, IL1B, S100A9, and S100A12 in the serum of AMI patients compared to normal individuals. Immunohistochemical staining of heart tissue from MI mice showed a progressive increase in the expression of CXCL8 and IL-1B as MI advanced, while S100A9 exhibited high expression at day 3 post-MI. mRNA expression analysis validated these findings. Additionally, we explored the skin lesions of psoriasis patients and found significantly higher expression of CXCL8, IL-1B, S100A9, and S100A12 in the affected skin areas compared to unaffected regions. These results highlight the consistent upregulation of hub genes in both AMI and psoriasis patients, as well as in myocardial infarction mice, underscoring their potential as reliable markers for disease diagnosis. Moreover, molecular docking simulations revealed potential interactions between simvastatin and key target proteins, suggesting a potential therapeutic avenue. Overall, our study uncovers shared molecular signatures and potential therapeutic targets, providing a foundation for future investigations targeting common pathways in psoriasis and AMI.

Comparative transcriptome analysis of acne vulgaris, rosacea, and hidradenitis suppurativa supports high-dose dietary zinc as a therapeutic agent.

Acne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. Specifically, we identified multiple zinc-binding proteins (SERPINA1, S100A7, S100A8, S100A9 and KRT16) as consistently highly upregulated genes across all three diseases. Our hypothesis suggests that these proteins could bind and sequester zinc, potentially leading to localized zinc deficiency and heightened inflammation. We identified high-dose dietary zinc as a promising therapeutic approach and confirmed its effectiveness through validation in an acne mouse model.

Polygenic TB control and the sequence of innate/adaptive immune responses to infection: MHC-II alleles determine the size of the S100A8/9-producing neutrophil population.

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2-congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC-II) region from TB-susceptible H2j mice transferred onto the genetic background of the TB-resistant C57BL/6 (H2b) strain. Susceptible B6.I-9.3 mice differ from B6 progenitors by the alleles of their only classical MHC-II H2-Aß gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB-related phenotypes between mice of the two strains and (ii) decipher interactions between the H2-Aß and S100A8/9 genes. Here, we describe the dynamics of TB-related phenotypes differentiating B6.I-9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4+ T-cell population, an enlarged S100A8/9-positive neutrophil population and higher S100A8/9 serum levels in B6.I-9.3 mice collectively form the 'susceptible' phenotype before infection. An increase in IL-17 and a decrease in intrferon-gamma production by CD4+ T-cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9-producing neutrophils in lungs and spleens and the proportion of Th17 CD4+ T-cells in lungs are significantly lower in the presence of the MHC-II dominant 'resistant' b allele compared to the recessive 'susceptible' j/j genotype. This provides direct genetic evidence that MHC-II-regulated CD4+ T-cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity.