Role Of S100A9 Research Articles

The role of S100A8 and S100A9 in external auditory canal cholesteatoma

The role of S100A8 and S100A9 in external auditory canal cholesteatoma

S100 Calcium-Binding Protein A9, a Potential Novel Diagnostic Biomarker for Idiopathic Pulmonary Fibrosis.

Neutrophilic inflammation is a characteristic feature of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A9 (S100A9) is a neutrophil-derived protein involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF remains unclear. We used enzyme-linked immunosorbent assays to measure S100A9 levels in bronchoalveolar lavage fluid (BALF) and serum obtained from healthy controls (HCs) and patients with IPF, non-specific interstitial pneumonia, hypersensitivity pneumonitis, and sarcoidosis. Compared with HCs, BALF S100A9 levels were significantly higher in IPF patients (P < 0.001), patients with hypersensitivity pneumonitis (P = 0.043), and patients with nonspecific interstitial pneumonia (P < 0.001). The S100A9 level in BALF of 0.093 ng/mL could distinguish IPF patients from HCs, with a specificity of 78.8% and a sensitivity of 81.6%. Similarly, the S100A9 level in BALF of 0.239 ng/mL had a specificity of 64.7% and a sensitivity of 66.7% for distinguishing IPF patients from patients with other interstitial lung diseases. Additionally, BALF S100A9 levels were significantly correlated with neutrophil counts (r = 0.356, P < 0.001) in BALF. IPF patients with S100A9 levels in BALF > 0.533 ng/mL had lower survival rates, compared with patients who had levels ≤ 0.553 ng/mL (n = 49; hazard ratio [HR], 3.62; P = 0.021). Combination analysis revealed that IPF patients with S100A9 levels in BALF> 0.553 ng/mL or neutrophil percentages > 49.1% (n = 43) had significantly lower survival rates than patients with S100A9 levels in BALF ≤ 0.553 ng/mL and neutrophil percentages ≤ 49.1% (n = 41) (HR, 3.91; P = 0.014). Additionally, patients with serum S100A9 levels > 0.077 ng/mL (n = 29) had significantly lower survival rates than patients with levels ≤ 0.077 ng/mL (n = 53, HR, 2.52; P = 0.013). S100A9 was expressed on neutrophils and macrophages in BALF from IPF patients as well as α-smooth muscle actin positive cells in the lung tissues. S100A9 is involved in the development and progression of IPF. Moreover, S100A9 levels in BALF and serum may be surrogate markers for IPF diagnosis and survival prediction, particularly when analyzed in combination with neutrophil percentages.

Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity.

S100 proteins are small proteins that are only expressed in vertebrates. They are widely expressed in many different cell types and are involved in the regulation of calcium homeostasis, glucose metabolism, cell proliferation, apoptosis, inflammation and tumorigenesis. As members of the S100 protein subfamily of myeloid-related proteins, S100A8, S100A9 and S100A12 play a crucial role in resisting microbial infection and maintaining immune homeostasis. These proteins chelate the necessary metal nutrients of pathogens invading the host by means of 'nutritional immunity' and directly inhibit the growth of pathogens in the host. They interact with receptors on the cell surface to initiate inflammatory signal transduction, induce cytokine expression and participate in the inflammatory response and immune regulation. Furthermore, the increased content of these proteins during the pathological process makes them useful as disease markers for screening and detecting related diseases. This article summarizes the structure and function of the proteins S100A8, S100A9 and S100A12 and lays the foundation for further understanding their roles in infection, immunity and inflammation, as well as their potential applications in the prevention and treatment of infectious diseases.

CRISPR-Cas9 based knockout of S100A8 in mammary epithelial cells enhances cell proliferation and triggers oncogenic transformation via the PI3K-Akt pathway: Insights from a deep proteomic analysis

S100A8 is a calcium-binding protein with multiple functions, including being a chemoattractant for phagocytes and playing a key role in the inflammatory response. Its expression has been shown to influence epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer. However, the role of S100A8 in cell proliferation and differentiation remains unknown. In this study, we used the CRISPR-Cas9 system to knock out S100A8 in healthy mammary epithelial cells and investigated the resulting changes in proteome profiling and signaling pathways. Our results showed that S100A8 knockout led to an increase in cell proliferation and migration, reduced cell-cell adhesion, and increased apoptosis compared to wildtype cells. Proteomics data indicated that S100A8 significantly affects cell cycle progression, cell proliferation, and cell survival through the PI3K-Akt pathway. Furthermore, our findings suggest that S100A8 function is associated with Pten expression, a negative regulator of the PI3K-Akt pathway. These results indicate that S100A8 dysregulation in healthy cells can lead to altered cellular physiology and higher proliferation, similar to cancerous growth. Therefore, maintaining S100A8 expression is critical for preserving healthy cell physiology. This study provides novel insights into the role of S100A8 in cell proliferation and differentiation and its potential relevance to cancer biology. SignificanceThe study suggests that maintaining S100A8 expression is critical for preserving healthy cell physiology, and dysregulation of S100A8 in healthy cells can lead to altered cellular physiology and higher proliferation, similar to cancerous growth. Therefore, targeting the PI3K-Akt pathway or regulating Pten expression, a negative regulator of the PI3K-Akt pathway, may be potential strategies for cancer treatment by controlling S100A8 dysregulation. Additionally, S100A8 and S100A9 have been shown to promote metastasis of breast carcinoma by forming a metastatic milieu. However, the differential expression of S100A8 in tumors and its dual effects of antitumor and protumor make the relationship between S100A8 and tumors complicated. Currently, most research focuses on the function of S100A8 as a secretory protein in the microenvironment of tumors, and its function inside healthy cells without forming dimers remains unclear. Furthermore, the study provides insight into the role of S100A8 in cell proliferation and differentiation, which may have implications for other diseases beyond cancer. The functional role of S100A8 in normal mammary epithelial cells remains completely uncertain. Therefore, the objective of this study is to investigate the function of S100A8 on proliferation in mammary epithelial cells after its deletion and to elucidate the underlying proteins involved in downstream signaling. Our findings indicate that the deletion of S100A8 leads to excessive proliferation in normal mammary epithelial cells, reduces apoptosis, and affects cell-cell adhesion molecules required for cellular communication, resulting in a cancer-like phenotype.

Forkhead box A1 induces angiogenesis through activation of the S100A8/p38 MAPK axis in cutaneous wound healing

BackgroundThe association between S100 calcium-binding protein A8 (S100A8) and angiogenesis has been reported in previous reports. This study focuses on the roles of S100A8 in the angiogenesis of human dermal microvascular endothelial cells (HDMECs) and in cutaneous wound healing in mice.MethodsCandidate genes related to angiogenesis activity were screened using a GSE83582 dataset. The overexpression DNA plasmid of S100A8 was transfected into HDMECs to analyze its effect on cell proliferation, migration, and angiogenesis. Full-thickness skin wounds were induced on mice, followed by adenovirus treatments to analyze the function of gene alteration in wound healing and pathological changes. The upstream regulator of S100A8 was predicted by bioinformatics analysis and verified by luciferase and immunoprecipitation assays. The role of the forkhead box A1 (FOXA1)-S100A8 interaction in p38 MAPK activation and angiogenesis were validated by rescue experiments.ResultsS100A8 was identified as a gene significantly correlated with angiogenesis. The S100A8 upregulation promoted the proliferation, migration, and angiogenesis of HDMECs, and it promoted p38 MAPK phosphorylation. Treatment of SB203580, a p38 MAPK inhibitor, blocked the promoting effect of S100A8. FOXA1 was identified as an upstream factor of S100A8 promoting its transcription. FOXA1 overexpression in HDMECs increased p38 MAPK phosphorylation and enhanced the activity of cells, which were blocked by the S100A8 inhibition. Similar results were reproduced in vivo where FOXA1 overexpression accelerated whereas the S100A8 knockdown retarded the cutaneous wound healing in mice.ConclusionFOXA1 mediates the phosphorylation of p38 MAPK through transcription activation of S100A8, thereby inducing angiogenesis and promoting cutaneous wound healing.

New Insights into the Impact of Human Papillomavirus on Oral Cancer in Young Patients: Proteomic Approach Reveals a Novel Role for S100A8.

We performed MS-based proteomics profiling based on HPV status in OSCC in young patients, following biological characterization and cell assays to explore the proteome functional landscape. Thirty-nine proteins are differentially abundant between HPV (+) and HPV (-) OSCC. Among them, COPS3, DYHC1, and S100A8 are unfavorable for tumor recurrence and survival, in contrast to A2M and Serpine1, low levels of which show an association with better DFS. Remarkably, S100A8 is considered an independent prognostic factor for lower survival rates, and at high levels, it alters tumor-associated immune profiling, showing a lower proportion of M1 macrophages and dendritic cells. HPV (+) OSCC also displayed the pathogen-associated patterns receptor that, when activated, triggered the S100A8 and NFκB inflammatory responses. HPV (+) OSCC has a peculiar microenvironment pattern distinctive from HPV (-), involving the expression of pathogen-associated pattern receptors, S100A8 overexpression, and NFκB activation and responses, which has important consequences in prognosis and may guide therapeutic decisions.

Decreased S100A9 expression alleviates Clostridium perfringens beta2 toxin-induced inflammatory injury in IPEC-J2 cells.

S100 calcium-binding protein A9 (S100A9) is a commonly known pro-inflammatory factor involved in various inflammatory responses. Clostridium perfringens (C. perfringens ) type C is known to cause diarrhea in piglets. However, the role of S100A9 in C. perfringens type C-induced infectious diarrhea is unclear. Here, the S100A9 gene was overexpressed and knocked down in the IPEC-J2 cells, which were treated with C. perfringens beta2 (CPB2) toxin. The role of S100A9 in CPB2 toxin-induced injury in IPEC-J2 cells was assessed by measuring the levels of inflammatory cytokines, reactive oxygen species (ROS), lactate dehydrogenase (LDH), cell proliferation, and tight junction-related proteins. The results showed elevated expression of S100A9 in diarrhea-affected piglet tissues, and the elevation of S100A9 expression after CPB2 toxin treatment of IPEC-J2 was time-dependent. In CPB2 toxin-induced IPEC-J2 cells, overexpression of S100A9 had the following effects: the relative expression of inflammatory factors IL-6, IL8, TNF-α, and IL-1β was increased; the ROS levels and LDH viability were significantly increased; cell viability and proliferation were inhibited; the G0/G1 phase cell ratio was significantly increased. Furthermore, overexpression of S100A9 reduced the expression of tight junction proteins in CPB2-induced IPEC-J2 cells. The knockdown of S100A9 had an inverse effect. In conclusion, our results confirmed that S100A9 exacerbated inflammatory injury in CPB2 toxin-induced IPEC-J2 cells, inhibited cell viability and cell proliferation, and disrupted the tight junctions between cells. Thus, decreased S100A9 expression alleviates CPB2 toxin-induced inflammatory injury in IPEC-J2 cells.

S100A9 plays a key role in Clostridium perfringens beta2 toxin-induced inflammatory damage in porcine IPEC-J2 intestinal epithelial cells

BackgroundAs an important regulator of autoimmune responses and inflammation, S100A9 may serve as a therapeutic target in inflammatory diseases. However, the role of S100A9 in Clostridium perfringens type C infectious diarrhea is poorly studied. The aim of our study was to screen downstream target genes regulated by S100A9 in Clostridium perfringens beta2 (CPB2) toxin-induced IPEC-J2 cell injury. We constructed IPEC-J2 cells with S100A9 knockdown and a CPB2-induced cell injury model, screened downstream genes regulated by S100A9 using RNA-Seq technique, and performed functional enrichment analysis. The function of S100A9 was verified using molecular biology techniques.ResultsWe identified 316 differentially expressed genes (DEGs), of which 221 were upregulated and 95 were downregulated. Functional enrichment analysis revealed that the DEGs were significantly enriched in cilium movement, negative regulation of cell differentiation, immune response, protein digestion and absorption, and complement and coagulation cascades. The key genes of immune response were TNF, CCL1, CCR7, CSF2, and CXCL9. When CPB2 toxin-induced IPEC-J2 cells overexpressed S100A9, Bax expression increased, Bcl-2 expression and mitochondrial membrane potential decreased, and SOD activity was inhibited.ConclusionIn conclusion, S100A9 was involved in CPB2-induced inflammatory response in IPEC-J2 cells by regulating the expression of downstream target genes, namely, TNF, CCL1, CCR7, CSF2, and CXCL9; promoting apoptosis; and aggravating oxidative cell damage. This study laid the foundation for further study on the regulatory mechanism underlying piglet diarrhea.

Inhibition of S100A9 function has immunomodulatory and cardioprotective effects in experimental autoimmune myocarditis

Background and Aims : Autoimmune myocarditis is characterized by non-ischemic inflammatory heart injury, leading to myocardial damage and impaired cardiac function. S100A9 is an inflammatory alarmin present in large amounts in neutrophils. The role of S100A9 as a potential treatment target in myocarditis has not been fully explored. We sought to investigate the impact of S100A9 blockade in experimental autoimmune myocarditis and assess the effects of treatment on cardiac function and immune infiltration.

S100A8 inhibition in leukemic lymphoblasts induces sensitivity to chemotherapy and inhibition of disease relapse.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and relapsed B-ALL is the leading cause of mortality in children with leukemia due to a lack of response to treatment. S100A8 is a low molecular weight calcium-binding intracellular protein that is expressed in certain cells, and its increased expression is seen in most tumors as well as in relapsed childhood B-ALL cases. The present study indicates the important role of S100A8 in improving viability and resistance to chemotherapy in relapsed B-ALL lymphoblasts. S100A8 levels were compared in B-ALL and relapsed B-ALL lymphoblasts that were sensitive and resistant to Vincristine, respectively. S100A8 was inhibited in the lymphoblasts of two patients by antisense locked nucleic acid (LNA) GapmeRs and the decreased expression of S100A8 was evaluated using quantitative real-time PCR and ELISA. Then, the S100A8 antisense LNA GapmeRs-transfected cells were treated with Vincristine and the expression levels of S100A8 mRNA and S100A8 protein were re-determined. At all of these stages, cell viability and LC50 were assessed by MTT assay. The results showed that S100A8 levels in relapsed B-ALL lymphoblasts were significantly higher than B-ALL lymphoblasts. Moreover, the increase in S100A8 expression was proportionate to the increase in Vincristine resistance in these cells. The S100A8 knockdown procedure using antisense LNA GapmeRs decreased the cell viability and increased vincristine sensitivity in lymphoblasts of two patients, and it also increased the sensitivity to chemotherapy in relapsed B-ALL lymphoblasts. According to the findings of the present study, S100A8 is effective in developing lymphoblast resistance to chemotherapy, and its enhanced expression may contribute to shifting B-ALL into the relapse phase of the illness. As a result, S100A8 may be a valuable target for managing and improving relapses B-ALL.

S100A8 (rs3806232) gene polymorphism and S100A8 serum level in psoriasis vulgaris patients: A preliminary study.

S100A8single nucleotide polymorphism (SNP) and S100A8 blood level are related to many inflammatory disorders with no available conclusion in psoriasis. The aim of this study was to evaluate the possible role of S100A8 in psoriasis pathogenesis through analyzing its S100A8 (rs3806232) gene polymorphism and S100A8serum level in psoriasis vulgaris patients, in addition to correlate the detected results with severity psoriasis in those patients. This case-control study was conducted on 50 patients having psoriasis vulgaris, and 26 controls. Severity of psoriasis was evaluated using psoriasis area and severity index (PASI) score. S100A8serum level and S100A8 (rs3806232) SNP were evaluated by ELISA and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) respectively. Serum S100A8level was significantly higher in psoriatic patients than controls and was positively correlated with PASI score (r=0.826, p<0.001). S100A8 (rs3806232) AA genotype and A allele were significantly increased among psoriasis patients than controls (p<0.001) increasing risk of psoriasis development by about 5, 12, and 6 times than AG, GG, and G alleles. AA genotype was significantly associated with psoriasis severity (p=0.005) and high S100A8serum levels (p=0.018). Circulating S100A8 could associated with disease severity and have an active role in psoriasis pathogenesis. S100A8 (rs3806232) SNP (AA genotype and A allele) might contribute to development and severity of psoriasis in the Egyptian population.

Evaluation of S100A12 and Apo-A1 plasma level potency in untreated new relapsing\u2013remitting multiple sclerosis patients and their family members

Multiple sclerosis is an inflammatory disease of the spinal cord and brain. Receptor for advanced glycation end products and Apolipoprotein A1 (Apo-AI) have been recommended to have a pathogenic role in the neuroinflammatory disorder as multiple sclerosis. The purpose of this research was to measure the plasma levels of S100A12 and Apo-A1 in the first-degree family of relapsing–remitting multiple sclerosis (RRMS) patients. Plasma levels of S100A12 & Apo-A1 were evaluated via enzyme-linked immunosorbent assay in the thirty-five new cases of untreated patients with deterministic RRMS according to the McDonald criteria, twenty-four healthy controls, and twenty-six first-degree members of untreated RRMS patients (called them as high-risk group). The main findings of this study were as follows: the plasma level of S100A12 was significantly lower in the new cases of untreated RRMS (P ≤ 0.05; 0.045) and high-risk (P ≤ 0.05; 0.001) groups. Although the plasma protein level of Apo-A1 was reduced significantly in the high-risk group (P < 0.05, P = 0.003) as compared to the healthy control group, there was no significant difference in the untreated RRMS patients (P = 0.379). The plasma level of vitamin D3 in both RRMS patients and high-risk groups displayed significance reduction, although, there was no significant association between vitamin D and S100A12 & Apo-A1 levels. Given the role of S100A12 and Apo-A1 in the inflammatory process performed in the first-degree family members of the RRMS patients, which revealed a significant decrease in this group, we concluded that they can be considered as one of the contributing factors in the pathogenesis of MS, though more research is needed before assuming them as predictive biomarkers.

Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis.

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

Abstract 10505: S100a12 Aggravates Acute Myocardial Infarction Injury Through Excessive Neutrophil Extracellular Trap Formation

Introduction: S100A12 represents a novel biomarker and therapeutic target that regulates cardiovascular disease after its release from myeloid cells. However, the role of S100A12 in the etiology of Acute Myocardial Infarction (AMI) is not well understood. Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of AMI and in the externalization of some S100 family members. Here, we investigated the effect of S100A12 on neutrophils’ function and myocardial injury after AMI. Methods and Results: Since S100A12 is a human specific molecule and not expressed in mice, we constructed transgenic (TG) mice expressing S100A12 in myeloid cells. By left anterior descending artery ligation and flow cytometry, we found that S100A12 markedly increased neutrophil infiltration and myocardial injury in TG mice compared to WT mice. Within the infarct zone, more neutrophil extracellular traps (NETs) were observed in TG mice, whereas intraperitoneal injection of DNase I decreased the damage effect of NETs. We used the overexpressing plasmid of S100A12 and observed that S100A12 enhanced the level of NETosis. Whereas, siRNA-mediated S100A12 silencing reduced the production of NETs. By ChIP and dual-luciferase reporter assay we found that Hypoxia-inducible factor-1α (HIF1α) directly bound to the promoter of the S100A12 gene and regulated S100A12 expression. We next used tandem mass tag (TMT) labeling quantitative proteomic technology and discovered that annexin a5 (ANXA5) was a receptor with significantly different expression level in TG compared with WT mice. Finally, we demonstrated that S100A12 increased NETs formation via receptor RAGE and ANXA5. Conclusions: Our findings reveal a critical role of S100A12 in regulating neutrophil activation and NETs formation, resulting in aggravated myocardial injury after AMI. In such a process, S100A12 regulates NETosis via the Hif1α-S100A12-ANXA5/RAGE pathway. S100A12 is a useful molecular marker and possible target for treatment for AMI.

Associations of Serum S100A12 With Severity and Prognosis in Patients With Community-Acquired Pneumonia: A Prospective Cohort Study.

BackgroundPrevious studies indicated the calcium-binding protein S100A12 to be involved in the pathophysiology of pulmonary inflammatory diseases. However, the role of S100A12 has remained elusive in patients with community-acquired pneumonia (CAP). Therefore, the purpose of this prospective cohort study was to evaluate the association between serum S100A12 with severity and prognosis in CAP patients.MethodsTwo groups with either 239 CAP patients or 239 healthy controls were enrolled in our study. Fasting blood and clinical characteristics were collected. On admission, serum S100A12 was measured using enzyme-linked immunosorbent assay (ELISA).ResultsSerum S100A12 was increased in CAP patients compared to control subjects. Furthermore, serum S100A12 was elevated according to the severity of CAP. Correlative analysis suggested that the level of serum S100A12 was associated with blood routine indices, renal function markers, inflammatory cytokines and other clinical parameters among CAP patients. Additionally, linear and logistical regression analyses indicated that serum S100A12 was positively associated with CAP severity scores in CAP patients. In addition, the association of high serum S100A12 and prognosis was accessed using a follow-up research. Elevated serum S100A12 on admission increased the risk of death and hospital stay in CAP patients during hospitalization.ConclusionsElevated serum S100A12 on admission is positively associated with the severity and adverse prognosis in CAP patients, suggesting that S100A12 may involve in the pathophysiological process of CAP. The titre of serum S100A12 may be used as a biomarker for diagnosis and prognosis among CAP patients.

The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells

BackgroundA major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis.MethodsWe analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas.ResultsWe found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC.ConclusionsPSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

Abstract 362: Patients with cervical cancer display an increase in leukocytes and myeloid cells that express S100A9

Abstract Cervical cancer is the second most common type of cancer affecting women worldwide. Leukocytosis have been related with treatment failure in this pathology, associated with the induction and accumulation of myeloid derived suppressor cells (MDSC) in peripheral blood. S100A9 proved to be a useful marker to identify MDSC in whole blood from patients with cancer. In this study, we analyzed the number of leukocytes that express S100A9, dividing them according to monocytic (CD14+) or granulocytic (CD15+) myeloid populations in patients with locally advanced cervical cancer (Ptes) and compared to healthy donors (Crls). Methods: Peripheral blood samples collected from 11 Crls and 19 Ptes with cervical cancer (stage IB3-IVA) treated in our Institution between 2018 and 2020 with concurrent chemoradiotherapy (cisplatin) followed by brachytherapy. Blood samples (before treatment, before brachytherapy and post-treatment assessment) were obtained. Leukocytes from buffy coat fraction were isolated and stained for S100A9, CD14 and CD15 and then analyzed by flow cytometry. The predictive value of S100A9+ cells between Ptes and Crls was evaluated and associated with therapeutic response. Results: An increase in leukocytes, granulocytes and monocytes positives for S100A9+ were observed in peripheral blood from Ptes with cervical cancer before treatment compared to Crls. Leukocytes: mean Ptes-Crls: 67.7-48.6; p=0.0017. Granulocytes: mean Ptes-Crls: 62.5-45.9; p=0.0073. Monocytes: median Ptes-Crls: 4.62-2.58; p=0.043. We did not find significant differences in S100A9+ cells over treatment between groups. Tumor response was dichotomized as complete and insufficient response (persistence + progression), relating it to S100A9+ cells. Using a logistic regression model, we observed that the percentage of leukocytes and granulocytes S100A9+ exhibited a trend close to significance of being associated with tumor response [Leukocytes odds ratio (OR): 0.908, 95% confidence interval (CI): 0.819-1.006, p=0.06; Granulocytes OR: 0.907, 95% CI: 0.821-1.002, p=0.057]. In this way, it represents that only a 1% increase in S100A9+ leukocytes or granulocytes are associated with a 9% reduction of having a complete response. Conclusions: In our study, patients with locally advanced cervical cancer presented an increase in total leukocytes and myeloid cells that express S100A9. The relationship that seems to exist between S100A9+ leukocytes and granulocytes with tumor response may suggest that patients with high levels of these circulating cells could defined a higher risk population associated with therapeutic failure. Further analysis and a larger cohort of patients with cervical cancer will be necessary to assess the potential role of S100A9+ leukocytes and myeloid cells as predictive markers. Citation Format: Yanina Veronica Langle, Pablo Damian Cresta Morgado, Denise Belgorosky, Pablo Marenco, Pablo Menéndez, Valeria Cáceres, Andrea Aguilar, Marcela Ostojich, Laura Lay, Ana María Eiján, Eduardo Omar Sandes. Patients with cervical cancer display an increase in leukocytes and myeloid cells that express S100A9 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 362.

S100A8 and S100A9, both transcriptionally regulated by PU.1, promote epithelial-mesenchymal transformation (EMT) and invasive growth of dermal keratinocytes during scar formation post burn.

S100 calcium-binding protein A8 (S100A8) and S100A9 are small molecular weight calcium-binding regulatory proteins that have been involved in multiple chronic inflammatory diseases. However, the role of S100A8 and S100A9 in keratinocytes in wounded skin and how they are regulated during this process are still unclear. Here, we found that S100A8 and S100A9 were both upregulated in burn-wounded skins in vivo and thermal-stimulated epidermal keratinocytes in vitro, accompanied by increased levels of epithelial-mesenchymal transition (EMT). Then, we demonstrated that upregulation of S100A8 and S100A9 alone or together enhanced characteristics of EMT in normal keratinocytes, manifested by excessive proliferation rate, abnormal ability of cell invasion, and high expression levels of EMT marker proteins. The transcription factor PU box-binding protein (PU.1) bound to the promoter regions and transcriptionally promoted the expression of S100A8 and S100A9 both in the human and mice, and it had strong positive correlations with both S100A8 and S100A9 protein levels in burned skin in vivo. Moreover, PU.1 positively regulated expression of S100A8 and S100A9 in a dose-dependent manner, and enhanced EMT of keratinocytes in vitro. Finally, through the burn mouse model, we found that PU.1-/- mice displayed a lower ability of scar formation, manifested by smaller scar volume, thickness, and collagen content, which could be enhanced by S100A8 and S100A9. In conclusion, PU.1 transcriptionally promotes expression of S100A8 and S100A9, thus positively regulating epithelial-mesenchymal transformation (EMT) and invasive growth of dermal keratinocytes during scar formation post burn.

The associations of serum S100A9 with the severity and prognosis in patients with community-acquired pneumonia: a prospective cohort study

BackgroundPrevious studies found that S100A9 may involve in the pathophysiology of community-acquired pneumonia (CAP). However, the role of S100A9 was unclear in the CAP. The goal was to explore the correlations of serum S100A9 with the severity and prognosis of CAP patients based on a prospective cohort study.MethodsA total of 220 CAP patients and 110 control subjects were recruited. Demographic and clinical data were collected. Serum S100A9 and inflammatory cytokines were measured.ResultsSerum S100A9 was elevated in CAP patients on admission. Serum S100A9 was gradually elevated parallelly with CAP severity scores. Additionally, inflammatory cytokines were increased and blood routine parameters were changed in CAP patients compared with control subjects. Correlation analysis found that serum S100A9 was positively associated with CAP severity scores, blood routine parameters (WBC, NLR and MON) and inflammatory cytokines. Further, logistic regression analysis demonstrated that there were positive associations between serum S100A9 and CAP severity scores. Besides, the prognosis of CAP was tracked. Serum higher S100A9 on the early stage elevated the death of risk and hospital stay among CAP patients.ConclusionSerum S100A9 is positively correlated with the severity of CAP. On admission, serum higher S100A9 elevates the risk of death and hospital stay in CAP patients, suggesting that S100A9 may exert a certain role in the pathophysiology of CAP and regard as a serum diagnostic and managing biomarker for CAP.

Clinical Implications of S100A12 and Resolvin D1 Serum Levels, and Related Genes in Children with Familial Mediterranean Fever

AbstractThe aim of this article was to study the role of S100A12 and resolvin D1-related genes and serum levels in the diagnosis and detection of subclinical inflammation in children with familial Mediterranean fever (FMF) during the quiescent stage of the disease. Seventy-eight children with FMF during the silent state and 60 healthy control were studied. Serum S100A12 and resolvin D1 were quantitatively measured using enzyme-linked immunosorbent assay. In addition, the levels of C-reactive protein, erythrocyte sedimentation rate, and hemoglobin were determined. The clinical severity was evaluated. The link between the Mediterranean fever (MEFV) gene and the genes related to the two studied biomarkers was also assessed. Correlation between S100A12 and resolvin D1 and the clinical severity was assessed. The mean serum levels of S100A12 and resolvin D1 were 847.4 and 793.3, respectively, which were highly significantly increased (p = 0.001) compared with the controls (324.3 and 235.1, respectively). The receiver operating characteristic curve test showed that S100A12 had a sensitivity of 97.4% and specificity of 80% with cutoff value of 529.5, while resolvin D1 showed a sensitivity of 100% and specificity of 50% with cutoff value of 231.2. A correlation was detected between the clinical severity and S100A12 and resolvin D1. This study delineated that S100A12 and resolvin D1 are sensitive biomarkers to detect the degree of inflammation in children with FMF during the silent period. Consequently, we recommend adjusting the colchicine dose to ameliorate the disease's symptoms and to improve the quality of life in these patients.