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1.
Cell Mol Life Sci ; 80(1): 35, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36622452

RESUMO

Chemokine CXCL8 is a key facilitator of the human host immune response, mediating neutrophil migration, and activation at the site of infection and injury. The oxidative burst is an important effector mechanism which leads to the generation of reactive nitrogen species (RNS), including peroxynitrite. The current study was performed to determine the potential for nitration to alter the biological properties of CXCL8 and its detection in human disease. Here, we show peroxynitrite nitrates CXCL8 and thereby regulates neutrophil migration and activation. The nitrated chemokine was unable to induce transendothelial neutrophil migration in vitro and failed to promote leukocyte recruitment in vivo. This reduced activity is due to impairment in both G protein-coupled receptor signaling and glycosaminoglycan binding. Using a novel antibody, nitrated CXCL8 was detected in bronchoalveolar lavage samples from patients with pneumonia. These findings were validated by mass spectrometry. Our results provide the first direct evidence of chemokine nitration in human pathophysiology and suggest a natural mechanism that limits acute inflammation.


Assuntos
Interleucina-8 , Ácido Peroxinitroso , Humanos , Quimiocinas/metabolismo , Inflamação/metabolismo , Interleucina-8/metabolismo , Interleucina-8/farmacologia , Leucócitos/metabolismo , Neutrófilos , Ácido Peroxinitroso/farmacologia
2.
PLoS One ; 18(1): e0280615, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36689438

RESUMO

In pregnancy-associated malaria, chemokines such as CXCL-4, CXCL-13, CXCL-16, and CCL-24 play critical roles in leucocyte trafficking to tissue sites in the infected placenta where inflammatory reactions are active. However, how plasma levels of these chemokines associate with Plasmodium falciparum placental malaria and pregnancy outcomes remains not well understood. The present study analyzed the plasma levels of CXCL-4, CXCL-13, CXCL-16, and CCL-24 chemokines in matched peripheral, placental and cord blood in relation with placental malaria (PM), and with submicroscopic parasitaemia. This was a retrospective case-control study (1:3 ratio) involving samples from 134 women (34 PM+ and 100 PM-) enrolled at delivery at the Marie Reine Health Center in Yaoundé, Cameroon between June 2013 and October 2018. Samples were collected just after delivery and used to diagnose microscopic and submicroscopic Plasmodium falciparum infections. Submicroscopic infections were detected by reverse transcription LAMP whereas chemokine levels were determined by Magnetic Luminex Screening Assay. Overall, PM was associated with increased plasma levels of CXCL-13 and CXCL-16 and low levels of CXCL-4 and CCL-24 in both peripheral and placental blood (0.0002 ≤ p ≤ 0.042). Similarly, CCL-24 levels in peripheral and placental blood samples were significantly lower in submicroscopically infected women compared to healthy controls (p = 0.04 and 0.02, respectively). Maternal hemoglobin levels increased with peripheral plasma levels of CXCL-4 (p = 0.005), CXCL-16 (p = 0.03), and CCL-24 (p = 0.002) while birth weight was lower for babies born from women with high levels of peripheral CXCL-13 (p = 0.0006) and low levels of cord CXCL-4 and CCL-24 (p = 0.02 and 0.08, respectively). Together the data suggest that low levels of CXCL-4 and CCL-24 coupled with high plasma levels of CXCL-13 and for a lesser extend CXCL-16 represent signatures of PM in the study population. These findings are relevant for understanding the immunopathogenesis of PM and developing new therapeutic or preventive strategies against severe PM outcomes.


Assuntos
Malária Falciparum , Malária , Complicações Parasitárias na Gravidez , Gravidez , Feminino , Humanos , Placenta , Camarões , Estudos de Casos e Controles , Estudos Retrospectivos , Malária Falciparum/epidemiologia , Malária/complicações , Quimiocinas , Plasmodium falciparum
3.
Sci Rep ; 13(1): 1288, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690687

RESUMO

Toxoplasma gondii can infect the host brain and trigger neuroinflammation. Such neuroinflammation might persist for years if the infection is not resolved, resulting in harmful outcomes for the brain. We have previously demonstrated the efficacy of immunotherapy targeting the programmed cell death protein 1 (PD-1) pathway on clearance of Toxoplasma tissue cysts. We aimed to test whether parasite clearance would lead to the resolution of neuroinflammation in infected brains. We established chronic Toxoplasma infection in BALB/c mice using the cyst-forming Prugniaud strain. Mice then received αPD-L1 or isotype control antibodies. After completion of the therapy, mice were euthanized six weeks later. The number of brain tissue cysts, Toxoplasma-specific CD8 + T cell proliferation and IFN-γ secretion, serum cytokine and chemokine levels, and CNS inflammation were measured. In αPD-L1-treated mice, we observed reduced brain tissue cysts, increased spleen weight, elevated IFN-γ production by antigen-specific CD8 + T cells, and a general increase in multiple serum cytokines and chemokines. Importantly, αPD-L1-treated mice displayed attenuation of meningeal lymphocytes, reactive astrocytes, and C1q expression. The reduction in inflammation-related proteins is correlated with reduced parasite burden. These results suggest that promoting systemic immunity results in parasite clearance, which in turn alleviates neuroinflammation. Our study may have implications for some brain infections where neuroinflammation is a critical component.


Assuntos
Toxoplasma , Camundongos , Animais , Doenças Neuroinflamatórias , Receptor de Morte Celular Programada 1/metabolismo , Citocinas/metabolismo , Encéfalo/metabolismo , Quimiocinas/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos BALB C , Imunoterapia
4.
Emerg Infect Dis ; 29(2): 268-277, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36692327

RESUMO

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.


Assuntos
COVID-19 , Vírus da Febre Hemorrágica da Crimeia-Congo , Febre Hemorrágica da Crimeia , Linfo-Histiocitose Hemofagocítica , Adulto , Humanos , Criança , Febre Hemorrágica da Crimeia/tratamento farmacológico , Febre Hemorrágica da Crimeia/epidemiologia , Febre Hemorrágica da Crimeia/patologia , Turquia/epidemiologia , Pandemias , COVID-19/epidemiologia , Citocinas , Progressão da Doença , Quimiocinas , Interferons , Linfo-Histiocitose Hemofagocítica/epidemiologia
5.
Anticancer Res ; 43(2): 831-839, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36697076

RESUMO

BACKGROUND/AIM: Colorectal carcinoma is a commonly diagnosed malignancy. The chemoattractant protein chemerin was shown to regulate immune response, angiogenesis, and cell migration and has a role in gastrointestinal cancers. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) are expressed in the colon and here, their diagnostic and prognostic value in colorectal carcinoma was examined. PATIENTS AND METHODS: Chemerin and CMKLR1 protein were quantified by immunohistochemistry in tumor tissues of 86 patients with colorectal cancer. Associations with tumor stage, tumor grade, lymph node score, tumor recurrence, and survival were calculated. RESULTS: Chemerin was not detectable in 12%, low expressed in 55%, medium expressed in 27%, and highly abundant in 7% of the tumors. CMKLR1 protein levels were low in 25%, medium in 70%, and high in 5% of the tumors. Chemerin protein expression was slightly induced in larger tumors of males. CMKLR1 protein expression was modestly higher in the tumors of patients with local and/or distal disease recurrence. CMKLR1 and chemerin protein in colorectal cancer tissues were not related to tumor grade or lymph node score. CD3, CD4, and CD8 protein expression did not correlate with chemerin or CMKLR1. Tumor chemerin and CMKLR1 protein levels were similar in survivors and non-survivors. CONCLUSION: In colorectal carcinoma, chemerin and CMKLR1 proteins are weakly associated with tumor stage and tumor recurrence. Levels of these proteins in colorectal carcinoma tissues are not connected with patients' survival.


Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Masculino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Quimiocinas/metabolismo
6.
Alzheimers Res Ther ; 15(1): 17, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36670424

RESUMO

BACKGROUND: Neuroinflammatory factors, especially chemokines, have been widely reported to be involved in the pathogenesis of Alzheimer's disease (AD). It is unclear how chemokines are altered in AD, and whether dysregulation of chemokines is the cause, or the consequence, of the disease. METHODS: We initially screened the transcriptomic profiles of chemokines from publicly available datasets of brain tissues of AD patients and mouse models. Expression alteration of chemokines in the blood from AD patients was also measured to explore whether any chemokine might be used as a potential biomarker for AD. We further analyzed the association between the coding variants of chemokine genes and genetic susceptibility of AD by targeted sequencing of a Han Chinese case-control cohort. Mendelian randomization (MR) was performed to infer the causal association of chemokine dysregulation with AD development. RESULTS: Three chemokine genes (CCL5, CXCL1, and CXCL16) were consistently upregulated in brain tissues from AD patients and the mouse models and were positively correlated with Aß and tau pathology in AD mice. Peripheral blood mRNA expression of CXCL16 was upregulated in mild cognitive impairment (MCI) and AD patients, indicating the potential of CXCL16 as a biomarker for AD development. None of the coding variants within any chemokine gene conferred a genetic risk to AD. MR analysis confirmed a causal role of CCL5 dysregulation in AD mediated by trans-regulatory variants. CONCLUSIONS: In summary, we have provided transcriptomic and genomic evidence supporting an active role of dysregulated CXCL16 and CCL5 during AD development.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/patologia , Transcriptoma , Quimiocinas/genética , Biomarcadores , Genômica , Quimiocina CXCL16/genética , Quimiocina CXCL16/metabolismo
7.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674931

RESUMO

Trichosanthin (TCS) is a type I ribosome-inactivating protein extracted from the tuberous root of the plant Trichosanthes. TCS shows promising potential in clinical drug abortion, anti-tumor and immunological regulation. However, the molecular mechanisms of its anti-tumor and immune regulation properties are still not well discovered. In the present study, we investigated the anti-tumor activity of TCS in hepatocellular carcinoma (HCC), both in vitro and in vivo. Both HCC cell lines and xenograft tumor tissues showed considerable growth inhibition after they were treated with TCS. TCS provoked caspase-mediated apoptosis in HCC cells and xenograft tumor tissues. The recruitment of CD8+ T cells to HCC tissues and the expression of chemokines, CCL2 and CCL22, were promoted upon TCS treatment. In addition, TCS induced an upregulation of Granzyme B (GrzB), TNF-α and IFN-γ in HCC tissues, which are the major cytotoxic mediators produced by T cells. Furthermore, TCS also resulted in an increase of mannose-6-phosphate receptor (M6PR), the major receptor of GrzB, in HCC tissues. In summary, these results suggest that TCS perhaps increases T-cell immunity via promoting the secretion of chemokines and accelerating the entry of GrzB to HCC cells, which highlights the potential role of TCS in anti-tumor immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Tricosantina , Humanos , Tricosantina/farmacologia , Tricosantina/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Linfócitos T CD8-Positivos/metabolismo , Granzimas , Neoplasias Hepáticas/tratamento farmacológico , Quimiocinas/farmacologia
8.
World J Surg Oncol ; 21(1): 8, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647133

RESUMO

BACKGROUND: Propofol and sevoflurane are two commonly used perioperative anesthetics. Some studies have found that these anesthetic drugs affect tumorigenesis. Previous studies have mostly focused on in vitro experiments, and the specimens collected were mainly peripheral body fluids, lacking direct evidence of the impact of anesthetic drugs on human tissues. This study aimed to elucidate the effects of propofol and sevoflurane on lung cancer using next-generation sequencing through an in vivo experiment. METHODS: Patients were randomly assigned to a group receiving either propofol or sevoflurane during surgery. Then, the patients' tumor and paired normal samples were collected and sequenced by next-generation sequencing. Differentially expressed genes (DEG) were analyzed by two statistical models, followed by cluster analysis, PCA, Gene Ontology, and KEGG pathway analysis. Candidate genes were confirmed by qRT-PCR. RESULTS: The demographic data of the two study groups were not statistically significant. Through single-factor model analysis, 810 DEG in the propofol group and 508 DEG in the sevoflurane group were obtained. To better reflect the differential effects between propofol and sevoflurane while reducing the false-positive DEG, we used multifactor model analysis, which resulted in 124 DEG. In PCA and cluster analysis, four groups (propofol cancer group, propofol normal group, sevoflurane cancer group, sevoflurane normal group) were separated adequately, indicating the accuracy of the analysis. We chose seven significant pathways (cellular response to interleukin-1, chemokine-mediated signaling pathway, chemokine signaling pathway, cytokine-cytokine receptor interaction, inflammatory response, immune response, and TNF signaling pathway) for downstream analysis. Based on the pathway analysis, three candidate genes (CXCR1, CXCL8, and TNFAIP3) were chosen, and their qRT-PCR results were consistent with the sequencing results. CONCLUSIONS: Through RNA-seq analysis, the effects of propofol and sevoflurane during lung cancer resection were different, mainly in inflammatory-related pathways, which might be possibly by targeting CXCL8. TRIAL REGISTRATION: Trial registry number was ChiCTR1900026213 .


Assuntos
Anestésicos , Neoplasias Pulmonares , Éteres Metílicos , Propofol , Humanos , Sevoflurano/efeitos adversos , Propofol/efeitos adversos , Projetos Piloto , Éteres Metílicos/efeitos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Perfilação da Expressão Gênica , Quimiocinas
9.
FASEB J ; 37(2): e22765, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36607642

RESUMO

The first line of defense against respiratory viruses relies on the antiviral and proinflammatory cytokine response initiated in infected respiratory epithelial cells. The cytokine response not only restricts virus replication and spreading, but also orchestrates the subsequent immune response. The epithelial Dual Oxidase 2 (DUOX2) has recently emerged as a regulator of the interferon antiviral response. Here, we investigated the role of DUOX2 in the inflammatory cytokine response using a model of A549 cells deficient in DUOX2 generated using Crispr-Cas9 and infected by Sendai virus. We found that the absence of DUOX2 selectively reduced the induction of a restricted panel of 14 cytokines and chemokines secreted in response to Sendai virus by 20 to 89%. The secreted factors produced by epithelial cells upon virus infection promoted the migration, adhesion, and degranulation of primary human neutrophils, in part through the DUOX2-dependent secretion of TNF and chemokines. In contrast, DUOX2 expression did not impact neutrophil viability or NETosis, thereby highlighting a selective impact of DUOX2 in neutrophil functions. Overall, this study unveils previously unrecognized roles of epithelial DUOX2 in the epithelial-immune cells crosstalk during respiratory virus infection.


Assuntos
Neutrófilos , Vírus , Humanos , Oxidases Duais/genética , Oxidases Duais/metabolismo , Células Epiteliais/metabolismo , Citocinas/metabolismo , Antivirais/farmacologia , Quimiocinas/metabolismo
10.
Phytomedicine ; 109: 154579, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610150

RESUMO

BACKGROUND: Morus alba fruits (MAF) belong to the Moraceae family, which are known to be effective in treating diabetic, autoimmune, and hormonal diseases owing to its low toxicity. MAF, as excerpted from Donguibogam, a representative Korean medical encyclopedia protected by UNESCO, has been widely used to treat lumbago, arthritis, and diabetes. Based on these effects, MAF is investigated for unidentified effects of atopic dermatitis, characterized by complex etiology of skin barrier dysfunction, inflammation, and chronic pruritus. METHODS: The antioxidant, inflammatory, and immunomodulatory properties of MAF and its bioactive compounds have been widely reported. According to an examination of 1-chloro-2,4-dinitrobenzene-induced AD-like skin lesions in NC/Nga mice, AD symptoms, such as increased dermatitis score, scratching frequency, immunoglobulin E, trans-epidermal water loss, epidermal thickness, and infiltration of mast cells, were relieved by topical MAF administration. They effectively attenuated cytokines and chemokines, such as interleukin (IL)-4, IL-5, IL-6, IL-8, IL-13, IL-17A, IL-22, IL-1ß, tumor necrosis factor-α, thymic stromal lymphopoietin (TSLP), thymic- and activation-regulated chemokine, normal T cell expression, and macrophage-derived chemokine secretion at the mRNA level in TNF-α/IFN-γ induced HaCaT (human immortalized keratinocyte) cells. RESULTS: Both in vivo and in vitro models, MAF increased the expression of filaggrin, involucrin, and loricrin, as well as inhibited the activation of Janus kinase 2, signal transducer and activator of transcription proteins 1, and mitogen-activated protein kinase pathways, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38. Moreover, MAF reduced the expression of TSLP and periostin, which play important roles in skin pruritus as chronic pruritogenic factors. CONCLUSION: These data indicate that MAF could be used as a potential treatment for AD-like skin lesions by regulating the inflammatory response, improving physical skin barriers, and relieving symptomatic pruritus.


Assuntos
Dermatite Atópica , Humanos , Camundongos , Animais , Dermatite Atópica/patologia , Frutas , Prurido/tratamento farmacológico , Pele , Citocinas/metabolismo , Quimiocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Imunidade
11.
Proc Natl Acad Sci U S A ; 120(3): e2216458120, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36626557

RESUMO

The lack of techniques for noninvasive imaging of inflammation has challenged precision medicine management of acute respiratory distress syndrome (ARDS). Here, we determined the potential of positron emission tomography (PET) of chemokine-like receptor-1 (CMKLR1) to monitor lung inflammation in a murine model of lipopolysaccharide-induced injury. Lung uptake of a CMKLR1-targeting radiotracer, [64Cu]NODAGA-CG34, was significantly increased in lipopolysaccharide-induced injury, correlated with the expression of multiple inflammatory markers, and reduced by dexamethasone treatment. Monocyte-derived macrophages, followed by interstitial macrophages and monocytes were the major CMKLR1-expressing leukocytes contributing to the increased tracer uptake throughout the first week of lipopolysaccharide-induced injury. The clinical relevance of CMKLR1 as a biomarker of lung inflammation in ARDS was confirmed using single-nuclei RNA-sequencing datasets which showed significant increases in CMKLR1 expression among transcriptionally distinct subsets of lung monocytes and macrophages in COVID-19 patients vs. controls. CMKLR1-targeted PET is a promising strategy to monitor the dynamics of lung inflammation and response to anti-inflammatory treatment in ARDS.


Assuntos
Lesão Pulmonar Aguda , COVID-19 , Síndrome do Desconforto Respiratório , Humanos , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Quimiocinas/metabolismo , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Imagem Molecular , Receptores de Quimiocinas
12.
EBioMedicine ; 87: 104420, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36592514

RESUMO

BACKGROUND: Whether immunotherapy combined with different histone deacetylases (HDAC) inhibitors in refractory or relapsed natural killer/T-cell lymphoma (NKTCL) is superior to each agent is still lacking in head-to-head clinical trials or preclinical evidence. METHODS: NKTCL cell line xenograft models (CDX) in immunocompetent, human programmed cell death protein 1 (PD1) knock-in genetically engineered mice were used to investigate the combination effects. Different types and dosages of HDAC inhibitors were investigated. We explored the underlying mechanisms by RNA-sequencing and ChIP-sequencing. Two clinical cases treated with anti-PD1/chidamide were presented. FINDINGS: Anti-PD1/chidamide shows significant tumour rejection in two CDX models. RNA-seq and CHIP-seq revealed that chidamide is synergistic to enhance T-cell chemokine expression, augment the Ifn-γ response, and increase CD8 T-cell infiltration via histone modification. Ifn-γ neutralizing antibody can attenuate the efficacy of combination drugs. However, the anti-PD1/romidepsin failed to augment the Ifn-γ response. The expressions of Ifn-γ related gene set signatures are significantly correlated with tumour rejection in anti-PD1/chidamide. In the clinic, two NKTCL patients treated with the PD1/chidamide show promising efficacy and limited toxicity. INTERPRETATION: Anti-PD1/chidamide enhances T-cell chemokine expression and augments the IFN-γ response in preclinical NKTCL immunocompetent models. IFN-γ signatures may be good response biomarkers for the selection of potentially benefit patients. FUNDING: This study was supported by the Chinese National Major Project for New Drug Innovation (2017ZX09304015) and the Chinese Society of Clinical Oncology Research Fund (Y-BMS2019-026).


Assuntos
Linfoma de Células T , Linfoma , Animais , Camundongos , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Quimiocinas , Interferon gama/uso terapêutico , Anticorpos/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Histona Desacetilases , Linhagem Celular Tumoral
13.
PLoS Negl Trop Dis ; 17(1): e0011041, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36595532

RESUMO

BACKGROUND: The immunopathogenesis of dengue virus (DENV) infection remains incompletely understood. To increase our understanding of inflammatory response in non-severe dengue, we assessed longitudinal changes in the inflammatory proteome in patients with an acute DENV infection. METHODS: Using a multiplex proximity extension assay (PEA), we measured relative levels of 368 inflammatory markers in plasma samples from hospitalized patients with non-severe DENV infection in the acute (n = 43) and convalescence (n = 35) phase of the infection and samples of healthy controls (n = 10). RESULTS: We identified 203 upregulated and 39 downregulated proteins in acute versus convalescent plasma samples. The upregulated proteins had a strong representation of interferon (IFN) and IFN-inducible effector proteins, cytokines (e.g. IL-10, IL-33) and cytokine receptors, chemokines, pro-apoptotic proteins (e.g. granzymes) and endothelial markers. A number of differentially expressed proteins (DEPs) have not been reported in previous studies. Functional network analysis highlighted a central role for IFNγ, IL-10, IL-33 and chemokines. We identified different novel associations between inflammatory proteins and circulating concentrations of the endothelial glycocalyx disruption surrogate marker syndecan-1. Conclusion: This unbiased proteome analysis provides a comprehensive insight in the inflammatory response in DENV infection and its association with glycocalyx disruption.


Assuntos
Dengue , Interleucina-10 , Humanos , Interleucina-33 , Proteoma , Proteômica , Citocinas/metabolismo , Quimiocinas
14.
Sci Rep ; 13(1): 599, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635313

RESUMO

There is a lack of objective tools for monitoring treatment response in extrapulmonary tuberculosis (EPTB). This study aimed to explore the utility of inflammatory biomarkers from the dry blood spots (DBS) as a tool for monitoring treatment response in EPTB. In a prospective cohort study, 40 inflammatory biomarkers were investigated in DBS samples from 105 EPTB cases using a Luminex platform. The samples were taken before, and, at the end of the 2nd and 6th months of treatment. A total of 11 inflammatory host biomarkers changed significantly with treatment in all EPTB patients. CXCL9/MIG, CCL20, CCL23, CXCL10/IP-10, CXCL1, CXCL2, and CXCL8 significantly declined in our cohort of EPTB (48 TB pleuritis and 57 TB lymphadenitis) patients at both time points. A biosignature consisting of MIG, CCL23, and CXCL2, corresponded with the treatment response in 81% of patients in the 2nd month and 79% of patients at the end of treatment. MIG, CCL23, IP-10, and CXCL2 changed significantly with treatment in all patients including those showing partial clinical response at the 2nd month of treatment. The changes in the levels of inflammatory biomarkers in the DBS correspond with the treatment success and can be developed as a routine test in low-resource settings.


Assuntos
Tuberculose Pleural , Humanos , Biomarcadores , Quimiocina CXCL10 , Estudos Prospectivos , /diagnóstico , Tuberculose Pleural/sangue , Tuberculose Pleural/diagnóstico , Teste em Amostras de Sangue Seco , Quimiocinas/sangue
15.
J Trauma Acute Care Surg ; 94(2): 187-196, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36694330

RESUMO

INTRODUCTION: Multiple large clinical trauma trials have documented an increased susceptibility to infection after injury. Although neutrophils (polymorphonuclear leukocytes [PMNs]) were historically considered a homogeneous cell type, we hypothesized that injury could alter neutrophil heterogeneity and predispose to dysfunction. To explore whether trauma modifies PMN heterogeneity, we performed an observational mass-spectrometry-based cytometry study on total leukocytes and low-density PMNs found in the peripheral blood mononuclear cell fraction of leukocytes from healthy controls and trauma patients. METHODS: A total of 74 samples from 12 trauma patients, each sampled at 1 or more time points, and matched controls were fractionated and profiled by mass-spectrometry-based cytometry using a panel of 44 distinct markers. After deconvolution and conservative gating on neutrophils, data were analyzed using Seurat, followed by clustering of principal components. RESULTS: Eleven distinct neutrophil populations were resolved in control and trauma neutrophils based on differential protein surface marker expression. Trauma markedly altered the basal heterogeneity of neutrophil subgroups seen in the control samples, with loss of a dominant population of resting neutrophils marked by high expression of C3AR and low levels of CD63, CD64, and CD177 (cluster 1), and expansion of two alternative neutrophil populations, one of which is marked by high expression of CD177 with suppression of CD10, CD16, C3AR, CD63, and CD64 (cluster 6). Remarkably, following trauma, a substantially larger percentage of neutrophils sediment in the monocyte fraction. These low-density neutrophils bear markers of functional exhaustion and form a unique trauma-induced population (cluster 9) with markedly upregulated expression of active surface adhesion molecules (activated CD11b/CD18), with suppression of nearly all other surface markers, including receptors for formyl peptides, leukotrienes, chemokines, and complement. CONCLUSION: Circulating neutrophils demonstrate considerable evidence of functional heterogeneity that is markedly altered by trauma. Trauma induces evolution of a novel, exhausted, low-density neutrophil population with immunosuppressive features.


Assuntos
Antígenos CD18 , Neutrófilos , Humanos , Neutrófilos/metabolismo , Antígenos CD18/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos/metabolismo , Quimiocinas
16.
Cell Signal ; 102: 110556, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36503163

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most popular malignant carcinomas in the genitourinary system. As a novel tumor-related gene, X-C Motif Chemokine Ligand 2 (XCL2) was up-regulated in ccRCC. The current study aims to reveal the functional activity of XCL2 in ccRCC. METHODS: The transcriptome profiling, clinical parameters, and simple nucleotide variation profiles of ccRCC samples were obtained from the Cancer Genome Atlas (TCGA) database. The survival analysis, multivariate/univariate Cox analysis, correlation analysis, gene set enrichment analysis (GSEA), and tumor mutation burden (TMB) analysis were performed. Next, immune cell infiltration and immune functions were analyzed. Finally, the functions of XCL2 were investigated in Caki-1 and 786-O cells. RESULTS: Upregulated XCL2 was associated with worse overall survival of ccRCC and correlated to age, grade, stage, and T stage. Age, grade, and XCL2 were independent prognostic factors. Significant enrichment in apoptosis, DNA replication, and immune response was demonstrated by GSEA. XCL2 was not only tightly associated with immune cell infiltration, but also significantly linked with several immune functions. Moreover, patients, who had higher XCL2 expression, owned higher levels of TMB. Interestingly, XCL2 was positively correlated with common immune checkpoints. In vitro, XCL2 could inhibit apoptosis, and promote proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of Caki-1 and 786-O cells. CONCLUSIONS: In general, the current study suggested that XCL2 may participate in the progression of ccRCC. Importantly, XCL2 may be a potential new target of immunotherapy.


Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Ligantes , Quimiocinas , Neoplasias Renais/genética
17.
Int J Cardiol ; 372: 6-14, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36513282

RESUMO

BACKGROUND: Timely and appropriate transformation of macrophage phenotypes from proinflammatory to anti-inflammatory is essential for cardiac repair after myocardial infarction (MI). Chemokine-like receptor 1 (CMKLR1), which is expressed on macrophages, is regulated by proinflammatory and anti-inflammatory stimuli. However, the contribution of CMKLR1 to macrophage phenotypic transformation and the role it plays in modulating cardiac repair after MI remain unclear. METHODS: CMKLR1 knockout (CMKLR1-/-) mice were generated by CRISPR/Cas-mediated genome engineering. A model of murine MI was induced by permanent ligation along the left anterior descending artery. Cardiac function was evaluated by echocardiography. Infarct size and collagen deposition were detected by Masson's trichrome staining. Cardiac macrophages were obtained by fluorescence-activated cell sorting. The protein and mRNA expression of associated molecules was determined by Western blotting and qRT-PCR. RESULTS: We demonstrated that macrophages highly expressed CMKLR1 and accumulated in murine infarcted hearts during the anti-inflammatory reparative phase of MI. CMKLR1 deficiency impaired cardiac function, increased infarct size, induced maladaptive cardiac remodeling, and decreased long-term survival after MI. Furthermore, CMKLR1 deficiency impeded macrophage phenotypic transformation from M1 to M2 in vivo and in vitro. In addition, we demonstrated that CMKLR1 signaling through the PI3K/Akt/mTOR pathway stimulated C/EBPß activation while simultaneously limiting NF-κB activation, thereby promoting anti-inflammatory and prohibiting proinflammatory macrophage polarization. CONCLUSIONS: Our results reveal that CMKLR1 deficiency impedes macrophage phenotypic transformation and cardiac repair after MI involving the PI3K/AKT/mTOR pathway. CMKLR1 may thus represent a potential therapeutic target for MI.


Assuntos
Infarto do Miocárdio , Fosfatidilinositol 3-Quinases , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Macrófagos/metabolismo , Serina-Treonina Quinases TOR , Fenótipo , Quimiocinas/metabolismo , Miocárdio/metabolismo , Camundongos Endogâmicos C57BL
18.
FASEB J ; 37(1): e22632, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36468785

RESUMO

Peritoneal fibrosis (PF) is an irreversible complication of peritoneal dialysis (PD) that leads to loss of peritoneal membrane function. We investigated PD effluent and serum levels and the tissue expression of chemokine (C-C motif) ligand 8 (CCL8) in patients with PD. Additionally, we investigated their association with PF in a mouse model. Eighty-two end-stage renal disease (ESRD) patients with PD were examined. CCL8 levels were measured via enzyme-linked immunosorbent assays in PD effluents and serum and analyzed with peritoneal transport parameters. Human peritoneal mesothelial cells (hPMCs) were obtained from the PD effluents of 20 patients. Primary cultured hPMCs were treated with recombinant (r) transforming growth factor (TGF)-ß, and CCL8 expression was assessed via western blotting. As the duration of PD increased, the concentration of CCL8 in PD effluents significantly increased. Correlations between peritoneal transport parameters and dialysate CCL8 levels were observed. Western blotting analysis showed that CCL8 was upregulated via rTGF-ß treatment, accompanied by increases in markers of inflammation, fibrosis, senescence, and apoptosis in hPMCs after induction of fibrosis with rTGF-ß. Anti-CCL8 monoclonal antibody (mAb) treatment suppressed the rTGF-ß-induced increase in all analyzed markers. Immunohistochemical analysis revealed that CCL8 along with fibrosis- and inflammation-related markers were significantly increased in the PF mouse model. Functional blockade of CCL8 using a CCR8 inhibitor (R243) abrogated peritoneal inflammation and fibrosis in vivo. In conclusion, high CCL8 levels in PD effluents may be associated with an increased risk of PD failure, and the CCL8 pathway is associated with PF. CCL8 blockade can ameliorate peritoneal inflammation and fibrosis.


Assuntos
Fibrose Peritoneal , Peritonite , Animais , Camundongos , Humanos , Fibrose Peritoneal/prevenção & controle , Quimiocina CCL8 , Peritônio , Quimiocinas , Ligantes , Inflamação , Modelos Animais de Doenças
19.
Nat Rev Immunol ; 23(1): 6, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36517623
20.
Emerg Microbes Infect ; 12(1): 2157338, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36482706

RESUMO

Cytokine dynamics in patients with coronavirus disease 2019 (COVID-19) have been studied in blood but seldomly in respiratory specimens. We studied different cell markers and cytokines in fresh nasopharyngeal swab specimens for the diagnosis and for stratifying the severity of COVID-19. This was a retrospective case-control study comparing Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine ligand 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in 490 (327 patients and 163 control) nasopharyngeal specimens from 317 (154 COVID-19 and 163 control) hospitalized patients. Of the 154 COVID-19 cases, 46 died. Both total and normalized MPO, ADA, CCL22, TNFα, and IL-6 mRNA expression levels were significantly higher in the nasopharyngeal specimens of infected patients when compared with controls, with ADA showing better performance (OR 5.703, 95% CI 3.424-9.500, p < 0.001). Receiver operating characteristics (ROC) curve showed that the cut-off value of normalized ADA mRNA level at 2.37 × 10-3 had a sensitivity of 81.8% and specificity of 83.4%. While patients with severe COVID-19 had more respiratory symptoms, and elevated lactate dehydrogenase, multivariate analysis showed that severe COVID-19 patients had lower CCL22 mRNA (OR 0.211, 95% CI 0.060-0.746, p = 0.016) in nasopharyngeal specimens, while lymphocyte count, C-reactive protein, and viral load in nasopharyngeal specimens did not correlate with disease severity. In summary, ADA appears to be a better biomarker to differentiate between infected and uninfected patients, while CCL22 has the potential in stratifying the severity of COVID-19.


Assuntos
COVID-19 , Humanos , COVID-19/diagnóstico , Interleucina-6/genética , Fator de Necrose Tumoral alfa/genética , Estudos Retrospectivos , Adenosina Desaminase/genética , Adenosina Desaminase/análise , Adenosina Desaminase/metabolismo , Estudos de Casos e Controles , Peroxidase , Ligantes , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Citocinas , Quimiocinas , Nasofaringe , Quimiocina CCL22
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