Loss of CX3CR1 augments neutrophil infiltration into cochlear tissues after acoustic overstimulation

Background:: Neoantigens are newly formed antigens that have not been previously recognized by the immune system. They may arise from altered tumor proteins that form as a result of mutations. Although neoantigens have recently been linked to antitumor immunity in long-term survivors of cancers, such as melanoma and colorectal cancer, their prognostic and immune-modulatory role in many cancer types remains undefined. Objective: The purpose of this study is to identify prognostic markers for long-term extrahepatic cholangiocarcinoma (EHCC) survival. Methods: We investigated neoantigens in EHCC, a rare, aggressive cancer with a 5-year overall survival rate lower than 10%, using a combination of whole-exome sequencing (WES), RNA sequencing (RNA-seq), computational biophysics, and immunohistochemistry. Results: : Our analysis revealed a decreased neutrophil infiltration-related trend of high-quality neoantigen load with IC50 <500 nM (r=-0.445, P=0.043). Among 24 EHCC patients examined, we identified four long-term survivors with WDFY3 neoantigens and none with WDFY3 neoantigens in the short-term survivors. The WDFY3 neoantigens are associated with a lower infiltration of neutrophils (p=0.013), lower expression of CCL5 (p=0.025), CXCL9 (p=0.036) and TIGIT (p=0.016), and less favorable prognosis (p=0.030). In contrast, the prognosis was not significantly associated with tumor mutation burden, neoantigen load, or immune cell infiltration. Conclusion:: We suggest that the WDFY3 neoantigens may affect prognosis by regulating antitumor immunity and that the WDFY3 neoantigens may be harnessed as potential targets for immunotherapy of EHCC.

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Polyphenols as Potential Therapeutics for Pain and Inflammation in Spinal Cord Injury

Current Molecular Pharmacology ◽

10.2174/1874467213666201223111743 ◽

2020 ◽

Vol 13 ◽

Author(s):

Ashif Iqubal ◽

Musheer Ahmed ◽

Mohammad Kashif Iqubal ◽

Faheem Hyder Pottoo ◽

Syed Ehtaishamul Haque

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Side Effects ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Neutrophil Infiltration ◽

Matrix Metal ◽

Mediators Of Inflammation ◽

Major Player ◽

Cord Injury

: Spinal cord injury (SCI) and associated pain and inflammation caused by the trauma or infection is one of the serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factor but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts,pericytes, Schwann cells, meningeal cells are the major player in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases and serotonin that stimulate nerve endings and manifests the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, until now, these compounds have been studied in preclinical models and shown promising results but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.

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Necroptosis protects against exacerbation of acute pancreatitis

Cell Death and Disease ◽

10.1038/s41419-021-03847-w ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Michittra Boonchan ◽

Hideki Arimochi ◽

Kunihiro Otsuka ◽

Tomoko Kobayashi ◽

Hisanori Uehara ◽

...

Keyword(s):

Acute Pancreatitis ◽

Necrotizing Pancreatitis ◽

Neutrophil Infiltration ◽

Dependent Manner ◽

Protective Effects ◽

Interacting Protein ◽

Inflammatory Conditions ◽

Edematous Pancreatitis ◽

Genetic Deletion ◽

Dose Dependent

AbstractThe sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3−/− or Mlkl−/− mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3−/− mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl−/− mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl−/− mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.

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The endoribonuclease N4BP1 prevents psoriasis by controlling both keratinocytes proliferation and neutrophil infiltration

Cell Death and Disease ◽

10.1038/s41419-021-03774-w ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Chenliang Gou ◽

Wenkai Ni ◽

Panpan Ma ◽

Fengbo Zhao ◽

Zhou Wang ◽

...

Keyword(s):

Physiological Role ◽

Neutrophil Infiltration ◽

Proper Function ◽

Psoriatic Skin ◽

Epidermal Keratinocytes ◽

Keratinocyte Proliferation ◽

Proliferation And Differentiation ◽

Long Time ◽

Chronic Skin ◽

Upregulated Genes

AbstractPsoriasis is a common chronic skin disease, characterized by abnormal interplay between hyperproliferative epidermal keratinocytes and self-reactive immune cells with not fully addressed molecular mechanism. N4BP1 (NEDD4-binding protein 1) is considered as an immune regulator for a long time but its physiological role is not determined yet. Here, we found that the expression of N4BP1 in skin was highest among all 54 tested tissues, and its expression was further upregulated in psoriatic skin. N4BP1-deficient mice exhibited normal grossly, but developed severe and prolonged IMQ-induced psoriasis-like disease comparing to controls. N4BP1 mainly expressed in keratinocytes and located on nucleus. Up- but not downregulated genes in N4BP1-deficient skin were specifically enriched in keratinocyte proliferation and differentiation. The proliferation of N4BP1-deficient primary keratinocytes was faster compared to that of controls. The upregulated genes upon ablation of N4BP1 were highly enriched in targets of AP-1 transcription factor. Knocking out N4BP1 resulted in upregulation of JunB and FosB, and conversely, overexpression of N4BP1 greatly reduced their expression. Furthermore, N4BP1 binds with JunB and FosB encoding mRNAs and greatly reduces their stability. In addition, with a high expression in neutrophils, N4BP1 limits survival of neutrophils in blood and infiltration of neutrophils in psoriatic skin by targeting CXCL1, CCL20, and S100A8. These findings demonstrate that N4BP1 controls the proper function of keratinocytes and neutrophils by negatively regulating JunB, FosB, and CXCL1, respectively, and that is critical for psoriasis prevention.

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Short-term Effects of Metformin on Cardiac and Peripheral Blood Cells Following Cecal Ligation and Puncture-induced Sepsis

Drug Research ◽

10.1055/a-1322-7478 ◽

2020 ◽

Author(s):

Tina Didari ◽

Shokoufeh Hassani ◽

Maryam Baeeri ◽

Mona Navaei-Nigjeh ◽

Mahban Rahimifard ◽

...

Keyword(s):

Oxidative Stress ◽

Weight Loss ◽

Blood Cells ◽

Cell Injury ◽

Antioxidant Properties ◽

Cecal Ligation ◽

Neutrophil Infiltration ◽

Cardiac Cells ◽

Cecal Ligation And Puncture ◽

Blood Profile

Abstract Aim of the study Sepsis has well-documented inflammatory effects on cardiovascular and blood cells. This study is designed to investigate potential anti-inflammatory effects of metformin on cardiac and blood cells 12 and 24 h following cecal ligation and puncture (CLP)-induced sepsis. Methods For the purpose of this study, 36 male Wistar rats were divided into six groups: two groups underwent CLP, two groups underwent CLP and received metformin, and two groups only received sham operations. 12 h later, 18 rats (half of rats in each of the three aforementioned groups) were sacrificed and cardiac and blood cells were harvested. Subsequently, 12 h later, the rest of the rats were euthanatized. In all harvested blood and cardiac cells, oxidative stress indicators, antioxidant properties, count of blood cells, neutrophil infiltration, percentage of weight loss and pathological assessment were conducted. Results In our experiment, metformin elevated antioxidant levels, improved function of blood cells and percentage of weight loss. Moreover, in the groups which received metformin, oxidative stress and neutrophil infiltration markers were decreased significantly. Moreover, pathological investigations of cardiac cell injury were reduced in the metformin group. Conclusions Our findings suggest that in CLP induced sepsis model, metformin can improve the function of blood and cardiac cells through alleviating inflammation, improvement of anti-inflammation properties, and enhancement of blood profile, and all these effects are more pronounced after 24 h in comparison with 12 h after induction of sepsis.

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Deficiency of the chemokine receptor CXCR2 attenuates neutrophil infiltration and cortical damage following closed head injury

Neurobiology of Disease ◽

10.1016/j.nbd.2010.06.015 ◽

2010 ◽

Vol 40 (2) ◽

pp. 394-403 ◽

Cited By ~ 74

Author(s):

Bridgette D. Semple ◽

Nicole Bye ◽

Jenna M. Ziebell ◽

M. Cristina Morganti-Kossmann

Keyword(s):

Head Injury ◽

Chemokine Receptor ◽

Closed Head Injury ◽

Neutrophil Infiltration ◽

Cortical Damage ◽

Closed Head ◽

Chemokine Receptor Cxcr2

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AB0702 THE FREQUENCY OF INFLAMMATORY BOWEL DISEASES IN PATIENTS WITH ANKYLOSING SPONDYLITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3798 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1647.2-1647

Author(s):

G. Lukina ◽

P. Kulakova ◽

N. Savenkova ◽

E. Volnukhin ◽

A. Kovshik ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Longitudinal Study ◽

Ankylosing Spondylitis ◽

Disease Activity ◽

Bowel Disease ◽

Rapid Test ◽

Neutrophil Infiltration ◽

Fecal Calprotectin ◽

High Disease Activity ◽

Inflammatory Bowel

Background:Аnkylosing Spondylitis (AS) is closely associated with inflammatory bowel disease (IBD). About 6-46% of patients with IBD have various lesions of the musculoskeletal system [1]. 5-10% of patients with spondylarthritis (SpA) eventually develop IBD, with Crohn’s disease (CD) being more common than Ulcerative colitis (UC) [2]. Determining the level of fecal calprotectin (FC) is a study that allows to diagnose IBD. The concentration of FC directly depends on the neutrophil infiltration of the intestinal mucosa and has a direct connection with the activity of the inflammatory process [3]. It is known that level of FC increases in 2/3 of patients with AS and is closely related to parameters reflecting higher disease activity [4].Objectives:The aim of this study was to evaluate the frequency of IBD in patients with AS using an assessment of FC level.Methods:In the analysis were included 40 patients with AS, fulfilling the modified New York criteria, among them man -26 (65%), woman -14 (35%), mean age of patients was 41.2 ±10.5, mean disease duration - 13±8.8 years. All patients were examined with ESR, CRP, esophagogastroduodenoscopy, colonoscopy and quantitative analysis of the fecal calprotectin levels using the method of lateral immunochromatography with the BUHLMANN Quantum Blue rapid test. Standart range: 100-1800 µg /g.Results:All patients had a high disease activity, mean BASDAI was 5.2 ± 1.7, mean ASDAS CRP 3.8 ± 1.1. 35 patients (87.5 %) had FC level more than 100 µg / g, the remaining 5 patients (12.5%) less than 100 µg /g. 12 patients (30 %) had FC level more than 1,800 µg / g, 23 (57.5 %) from 101 µg / g to 1800 µg / g. All patients with FC levels more than 100 µg / g showed an increase CRP (mean 28.4 mg / l) and ESR (mean 36.3 mm\h) levels. IBD were diagnosed in 9 cases (22.5%): 5 patients (12.5 %) with CD and 4 patients (10 %) - UC, in the remaining cases (77.5%) was no intestinal pathology.Conclusion:The results showed high frequency of IBD in patients with AS. Patients with high FC levels (more than 100 μg/g) had high disease activity (AS). In most cases, inflammatory bowel disease were diagnosed in patients with FC levels more than 100 µg/g.References:[1] Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol. 2001 Apr;96(4):1116-22.[2] Klingberg, E., Strid, H., Stahl, A.et al. A longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitis. A longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitis. Arthritis Res Ther 2017. 19(1):21[3] Cypers H, Varkas G, Beeckman S, et al. Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis. Annals of the Rheumatic Diseases. 2016. 75:1357-1362[4] Arzu Duran, Senol Kobak, Nazime Sen, et al. Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis. Bosnian Journal of Basic Medical Sciences. 2016. 16 (1):71-4Disclosure of Interests:Galina Lukina Speakers bureau: Novartis, Pfizer, UCB, Abbvie, Biocad, MSD, Roche, Polina Kulakova: None declared, Nadezhda Savenkova: None declared, Evgeniy Volnukhin: None declared, Anton Kovshik: None declared, Elena Alexandrova: None declared, Alexandr Novikov: None declared

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