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1.
Front Immunol ; 12: 739757, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745109

RESUMO

Coronavirus disease 2019 (COVID-19) exhibits a sex bias with males showing signs of more severe disease and hospitalizations compared with females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV-2 have not been studied because of the gap in timing between the patient becoming infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of dendritic cells (DCs) and monocytes from males and females to SARS-CoV-2, 24 h after infection. To investigate this, peripheral blood mononuclear cells (PBMCs) from healthy young individuals were stimulated in vitro with the virus. Our results indicate that PBMCs from females upregulated the expression of HLA-DR and CD86 on pDCs and mDCs after stimulation with the virus, while the activation of these cells was not significant in males. Monocytes from females also displayed increased activation than males. In addition, females secreted significantly higher levels of IFN-α and IL-29 compared with males at 24 h. However, the situation was reversed at 1 week post stimulation and males displayed high levels of IFN-α production compared with females. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females at 24 h. The PBMCs from females also displayed increased induction of CTLs. Altogether, our results suggest that decreased activation of pDCs, mDCs, and monocytes and the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the increased morbidity and mortality of males to COVID-19.


Assuntos
COVID-19/imunologia , Células Dendríticas/imunologia , Leucócitos Mononucleares/imunologia , SARS-CoV-2/fisiologia , Imunidade Adaptativa , Adulto , Quimiocina CXCL1/metabolismo , Feminino , Antígenos HLA-DR/metabolismo , Voluntários Saudáveis , Humanos , Imunidade Inata , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais , Regulação para Cima , Adulto Jovem
2.
FASEB J ; 35(10): e21946, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34555226

RESUMO

Acute respiratory distress syndrome (ARDS) is a life-threatening illness characterized by decreased alveolar-capillary barrier function, pulmonary edema consisting of proteinaceous fluid, and inhibition of net alveolar fluid transport responsible for resolution of pulmonary edema. There is currently no pharmacotherapy that has proven useful to prevent or treat ARDS, and two trials using beta-agonist therapy to treat ARDS demonstrated no effect. Prior studies indicated that IL-8-induced heterologous desensitization of the beta2-adrenergic receptor (ß2 -AR) led to decreased beta-agonist-induced mobilization of cyclic adenosine monophosphate (cAMP). Interestingly, phosphodiesterase (PDE) 4 inhibitors have been used in human airway diseases characterized by low intracellular cAMP levels and increases in specific cAMP hydrolyzing activity. Therefore, we hypothesized that PDE4 would mediate IL-8-induced heterologous internalization of the ß2 -AR and that PDE4 inhibition would restore beta-agonist-induced functions. We determined that CINC-1 (a functional IL-8 analog in rats) induces internalization of ß2 -AR from the cell surface, and arrestin-2, PDE4, and ß2 -AR form a complex during this process. Furthermore, we determined that cAMP associated with the plasma membrane was adversely affected by ß2 -AR heterologous desensitization. Additionally, we determined that rolipram, a PDE4 inhibitor, reversed CINC-1-induced derangements of cAMP and also caused ß2 -AR to successfully recycle back to the cell surface. Finally, we demonstrated that rolipram could reverse CINC-1-mediated inhibition of beta-agonist-induced alveolar fluid clearance in a murine model of trauma-shock. These results indicate that PDE4 plays a role in CINC-1-induced heterologous internalization of the ß2 -AR; PDE4 inhibition reverses these effects and may be a useful adjunct in particular ARDS patients.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Interleucina-8/imunologia , Receptores Adrenérgicos beta 2/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Quimiocina CXCL1/metabolismo , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/farmacologia , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , beta-Arrestina 1/metabolismo
3.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299135

RESUMO

Adiponectin and leptin are two abundant adipokines with different properties but both described such as potent factors regulating angiogenesis. AdipoRon is a small-molecule that, binding to AdipoRs receptors, acts as an adiponectin agonist. Here, we investigated the effects of AdipoRon and leptin on viability, migration and tube formation on a human in vitro model, the human umbilical vein endothelial cells (HUVEC) focusing on the expression of the main endothelial angiogenic factors: hypoxia-inducible factor 1-alpha (HIF-1α), C-X-C motif chemokine ligand 1 (CXCL1), vascular endothelial growth factor A (VEGF-A), matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9). Treatments with VEGF-A were used as positive control. Our data revealed that, at 24 h treatment, proliferation of HUVEC endothelial cells was not influenced by AdipoRon or leptin administration; after 48 h longer exposure time, the viability was negatively influenced by AdipoRon while leptin treatment and the combination of AdipoRon+leptin produced no effects. In addition, AdipoRon induced a significant increase in complete tubular structures together with induction of cell migration while, on the contrary, leptin did not induce tube formation and inhibited cell migration; interestingly, the co-treatment with both AdipoRon and leptin determined a significant decrease of the tubular structures and cell migration indicating that leptin antagonizes AdipoRon effects. Finally, we found that the effects induced by AdipoRon administration are accompanied by an increase in the expression of CXCL1, VEGF-A, MMP-2 and MMP-9. In conclusion, our data sustain the active role of adiponectin and leptin in linking adipose tissue with the vascular endothelium encouraging the further deepening of the role of adipokines in new vessel's formation, to candidate them as therapeutic targets.


Assuntos
Adiponectina/farmacologia , Movimento Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Leptina/farmacologia , Neovascularização Fisiológica/fisiologia , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Am J Physiol Cell Physiol ; 321(3): C415-C428, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260299

RESUMO

Leucine-rich α-2-glycoprotein-1 (LRG1) is a novel profibrotic factor that modulates transforming growth factor-ß (TGF-ß) signaling. However, its role in the corneal fibrotic response remains unknown. In the present study, we found that the LRG1 level increased in alkali-burned mouse corneas. In the LRG1-treated alkali-burned corneas, there were higher fibrogenic protein expression and neutrophil infiltration. LRG1 promoted neutrophil chemotaxis and CXCL-1 secretion. Conversely, LRG1-specific siRNA reduced fibrogenic protein expression and neutrophil infiltration in the alkali-burned corneas. The clearance of neutrophils effectively attenuated the LRG1-enhanced corneal fibrotic response, whereas the presence of neutrophils enhanced the effect of LRG1 on the fibrotic response in cultured TKE2 cells. In addition, the topical application of LRG1 elevated interleukin-6 (IL-6) and p-Stat3 levels in the corneal epithelium and in isolated neutrophils. The clearance of neutrophils inhibited the expression of p-Stat3 and IL-6 promoted by LRG1 in alkali-burned corneas. Moreover, neutrophils significantly increased the production of IL-6 and p-Stat3 promoted by LRG1 in TKE2 cells. Furthermore, the inhibition of Stat3 signaling by S3I-201 decreased neutrophil infiltration and alleviated the LRG1-enhanced corneal fibrotic response in the alkali-burned corneas. S3I-201 also reduced LRG1 or neutrophil-induced fibrotic response in TKE2 cells. In conclusion, LRG1 promotes the corneal fibrotic response by stimulating neutrophil infiltration via the modulation of the IL-6/Stat3 signaling pathway. Therefore, LRG1 could be targeted as a promising therapeutic strategy for patients with corneal fibrosis.


Assuntos
Queimaduras Químicas/genética , Quimiotaxia/efeitos dos fármacos , Queimaduras Oculares/genética , Glicoproteínas/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Álcalis , Ácidos Aminossalicílicos/farmacologia , Animais , Benzenossulfonatos/farmacologia , Queimaduras Químicas/tratamento farmacológico , Queimaduras Químicas/metabolismo , Queimaduras Químicas/patologia , Linhagem Celular , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Epitélio Corneano/patologia , Queimaduras Oculares/induzido quimicamente , Queimaduras Oculares/tratamento farmacológico , Queimaduras Oculares/patologia , Fibrose/prevenção & controle , Regulação da Expressão Gênica , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
5.
Nat Immunol ; 22(8): 947-957, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239121

RESUMO

One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Quimiocina CXCL1/metabolismo , Neoplasias Colorretais/imunologia , Células Supressoras Mieloides/imunologia , Receptor 2 Toll-Like/imunologia , Microambiente Tumoral/imunologia , Alarminas/genética , Alarminas/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7
6.
Phytomedicine ; 90: 153628, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34247114

RESUMO

BACKGROUND: Metastasis is the most common lethal cause of breast cancer-related death. Recent studies have implied that autophagy is closely implicated in cancer metastasis. Therefore, it is of great significance to explore autophagy-related molecular targets involved in breast cancer metastasis and to develop therapeutic drugs. PURPOSE: This study was designed to investigate the anti-metastatic effects and autophagy regulatory mechanisms of Aiduqing (ADQ) formula on breast cancer. STUDY DESIGN/METHODS: Multiple cellular and molecular experiments were conducted to investigate the inhibitory effects of ADQ formula on autophagy and metastasis of breast cancer cells in vitro. Meanwhile, autophagic activator/inhibitor as well as CXCL1 overexpression or interference plasmids were used to investigate the underlying mechanisms of ADQ formula in modulating autophagy-mediated metastasis. Furthermore, the zebrafish xenotransplantation model and mouse xenografts were applied to validate the inhibitory effect of ADQ formula on autophagy-mediated metastasis in breast cancer in vivo. RESULTS: ADQ formula significantly inhibited the proliferation, migration, invasion and autophagy but induced apoptosis of high-metastatic breast cancer cells in vitro. Similar results were also observed in starvation-induced breast cancer cells which exhibited elevated metastatic ability and autophagy activity. Mechanism investigations further approved that either CXCL1 overexpression or autophagic activator rapamycin can significantly abrogated the anti-metastatic effects of ADQ formula, suggesting that CXCL1-mediated autophagy may be the crucial pathway of ADQ formula in suppressing breast cancer metastasis. More importantly, ADQ formula suppressed breast cancer growth, autophagy, and metastasis in both the zebrafish xenotransplantation model and the mouse xenografts. CONCLUSION: Our study not only revealed the novel function of CXCL1 in mediating autophagy-mediated metastasis but also suggested ADQ formula as a candidate drug for the treatment of metastatic breast cancer.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias da Mama , Quimiocina CXCL1/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Metástase Neoplásica/prevenção & controle , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
8.
Am J Physiol Gastrointest Liver Physiol ; 321(2): G157-G170, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132111

RESUMO

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.NEW & NOTEWORTHY Obese Zucker rats, which are resistant to leptin, exhibit a diminished inflammatory response in the trinitrobenzenesulfonic acid (TNBS) model of colitis, suggesting leptin role is proinflammatory. At the same time, obese Zucker rats present a debilitated intestinal barrier function, with increased translocation of LPS. Zucker rats present a dual response in the TNBS model of rat colitis.


Assuntos
Colite Ulcerativa/metabolismo , Mucosa Intestinal/metabolismo , Leptina/metabolismo , Lipopolissacarídeos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Calgranulina A/metabolismo , Quimiocina CXCL1/metabolismo , Colite Ulcerativa/etiologia , Colite Ulcerativa/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Absorção Intestinal , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Zucker , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Fator de Transcrição STAT3/metabolismo , Proteínas de Junções Íntimas/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067897

RESUMO

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Fatores Etários , Consumo de Bebidas Alcoólicas/imunologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Animais , Animais não Endogâmicos , Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Quimiocina CXCL1/metabolismo , Dieta Hiperlipídica , Etanol/farmacologia , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Obesidade , Autoadministração/métodos
10.
PLoS One ; 16(5): e0251809, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34029331

RESUMO

The dendritic cell (DC)-derived cytokine profile contributes to naive T cell differentiation, thereby directing the immune response. IL-37 is a cytokine with anti-inflammatory characteristics that has been demonstrated to induce tolerogenic properties in DC. In this study we aimed to evaluate the influence of IL-37 on DC-T cell interaction, with a special focus on the role of the chemokine CXCL1. DC were cultured from bone marrow of human IL-37 transgenic (hIL-37Tg) or WT mice. The phenotype of unstimulated and LPS-stimulated DC was analyzed (co-stimulatory molecules and MHCII by flow cytometry, cytokine profile by RT-PCR and ELISA), and T cell stimulatory capacity was assessed in mixed lymphocyte reaction. The role of CXCL1 in T cell activation was analyzed in T cell stimulation assays with anti-CD3 or allogeneic DC. The expression of the co-stimulatory molecules CD40, CD80 and CD86, and of MHCII in LPS-stimulated DC was not affected by endogenous expression of IL-37, whereas LPS-stimulated hIL-37Tg DC produced less CXCL1 compared to LPS-stimulated WT DC. T cell stimulatory capacity of LPS-matured hIL-37Tg DC was comparable to that of WT DC. Recombinant mouse CXCL1 did not increase T cell proliferation either alone or in combination with anti-CD3 or allogeneic DC, nor did CXCL1 affect the T cell production of interferon-γ and IL-17. Endogenous IL-37 expression does not affect mouse DC phenotype or subsequent T cell stimulatory capacity, despite a reduced CXCL1 production. In addition, we did not observe an effect of CXCL1 in T cell proliferation or differentiation.


Assuntos
Comunicação Celular/imunologia , Quimiocina CXCL1/metabolismo , Células Dendríticas/metabolismo , Interleucina-1/metabolismo , Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Proliferação de Células , Células Cultivadas , Quimiocina CXCL1/genética , Células Dendríticas/imunologia , Humanos , Interleucina-1/genética , Ativação Linfocitária , Masculino , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
11.
PLoS One ; 16(5): e0250862, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33945545

RESUMO

Resolvin D1, a specialized pro-resolving lipid mediator produced from docosahexaenoic acid by 15- and 5-lipoxygenase, exerts anti-inflammatory effects driving to the resolution of inflammation. The present study aimed to elucidate its role in small intestinal damage induced by nonsteroidal anti-inflammatory drug (NSAID). Indomethacin was administered orally to C57BL/6J male mice, which were sacrificed 24 h later to collect small intestine specimens. Before administration of indomethacin, mice were subjected to intraperitoneal treatment with resolvin D1 or oral administration of baicalein, a 15-lipoxygenase inhibitor. Small intestinal damage induced by indomethacin was attenuated by pretreatment with resolvin D1. Furthermore, resolvin D1 reduced the gene expression levels of interleukin-1ß, tumor necrosis factor-α, and CXCL1/keratinocyte chemoattractant. Conversely, the inhibition of 15-lipoxygenase activity by baicalein increased the expression of genes coding for these inflammatory cytokines and chemokine, leading to exacerbated small intestinal damage, and reduced the concentration of resolvin D1 in the small intestinal tissue. Exogenous treatment with resolvin D1 negated the deleterious effect of baicalein. 15-lipoxygenase was mainly expressed in the epithelium and inflammatory cells of the small intestine, and its gene and protein expression was not affected by the administration of indomethacin. Inhibition of the resolvin D1 receptor, lipoxin A4 receptor /formyl peptide receptor 2, by its specific inhibitors Boc-1 and WRW4 aggravated indomethacin-induced small intestinal damage. Collectively, these results indicate that resolvin D1 produced by 15-lipoxygenase contributes to mucoprotection against NSAID-induced small intestinal damage through its anti-inflammatory effect.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Inflamação/tratamento farmacológico , Intestino Delgado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Quimiocina CXCL1/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Lipídeos , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Preparações Farmacêuticas
12.
Front Immunol ; 12: 636818, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34040603

RESUMO

In addition to regulating immune responses by producing antibodies that confer humoral immunity, B cells can also affect these responses by producing cytokines. How B cells participate in the clearance of pathogenic infections via functions other than the production of pathogen-specific antibodies is still largely unknown. Marginal zone (MZ) B cells can quickly respond to bacterial invasion by providing the initial round of antibodies. After a bloodborne bacterial infection, neutrophils promptly migrate to the MZ. However, the mechanisms regulating neutrophil accumulation in the MZ during the initial phase of infection also remain obscure. Here, we found that MZ B cell-deficient mice are more susceptible to systemic Staphylococcus aureus (S. aureus) infection compared with wildtype mice. The expression levels of interleukin (IL)-6 and CXCL1/CXCL2 in MZ B cells increased significantly in mice at 3-4 h after infection with S. aureus, then decreased at 24 h post-infection. After systemic S. aureus infection, splenic neutrophils express increased CXCR2 levels. Our results from confocal microscopy imaging of thick-section staining demonstrate that neutrophils in wildtype mice form cell clusters and are in close contact with MZ B cells at 3 h post-infection. This neutrophil cluster formation shortly after infection was diminished in both MZ B cell-deficient mice and IL-6-deficient mice. Blocking the action of CXCL1/CXCL2 by injecting anti-CXCL1 and anti-CXCL2 antibodies 1 h before S. aureus infection significantly suppressed the recruitment of neutrophils to the MZ at 3 h post-infection. Compared with peptidoglycan stimulation alone, peptidoglycan stimulation with neutrophil co-culture further enhanced MZ B-cell activation and differentiation. Using a Förster resonance energy transfer by fluorescence lifetime imaging (FLIM-FRET) analysis, we observed evidence of a direct interaction between neutrophils and MZ B cells after peptidoglycan stimulation. Furthermore, neutrophil depletion in mice resulted in a reduced production of S. aureus-specific immunoglobulin (Ig)M at 24 h post-infection. Together, our results demonstrate that MZ B cells regulate the rapid neutrophil swarming into the spleen during the early phase of systemic S. aureus infection. Interaction with neutrophils assists MZ B cells with their differentiation into IgM-secreting cells and contributes to the clearance of systemic bacterial infections.


Assuntos
Linfócitos B/imunologia , Interleucina-6/metabolismo , Neutrófilos/imunologia , Baço/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Animais , Bacteriemia , Diferenciação Celular , Células Cultivadas , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Doenças do Sistema Imunitário , Imunidade Celular , Interleucina-6/genética , Transtornos Leucocíticos , Ativação Linfocitária , Camundongos , Camundongos Knockout , Peptidoglicano/imunologia
14.
FASEB J ; 35(4): e21354, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33749892

RESUMO

ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12-hydroxyeicosapentaenoic acid (12-HEPE), which is a 12-lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid-rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12-HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12-HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12-HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12-HEPE as the dominant ω3 fatty acid metabolite in the skin.


Assuntos
Quimiocina CXCL1/metabolismo , Dermatite de Contato/prevenção & controle , Ácido Eicosapentaenoico/análogos & derivados , Queratinócitos/efeitos dos fármacos , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/metabolismo , Células da Medula Óssea , Quimiocina CXCL1/genética , Dieta , Dinitrofluorbenzeno , Regulação para Baixo , Ácido Eicosapentaenoico/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células HaCaT , Humanos , Óleo de Semente do Linho/administração & dosagem , Óleo de Semente do Linho/metabolismo , Camundongos
15.
Mol Cell Biochem ; 476(8): 2989-2998, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33770315

RESUMO

Angiogenesis is critical to establishing a successful pregnancy. The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small cytokine belonging to the CXC chemokine family that is an important chemokine involved in the processes of angiogenesis and arteriogenesis; however, little is known about its role in decidual angiogenesis. Effects of CXCL1 on cell proliferation and migration (propidium iodide staining and wound healing assays) of HUVEC cells were determined. The angiogenesis roles of CXCL1 in HUVEC-HTR8/SVneo co-culture system were detected by the tube formation assay. Signal transduction pathways in HUVEC cells in response to CXCL1 were determined by in-cell western analyses. In vivo, mice were injected with (1) PBS (Group A) or (2) CXCL1-neutralizing antibody (Group B) or (3) CXCL1-neutralizing antibody plus recombinant VEGF-A protein (Group C) from E1 to E5 and sacrificed at E6.5 of pregnancy. The decidual angiogenesis in mice was examined by immunohistochemistry of cluster designation 34 (CD34), and the expression levels of vascular endothelial growth factor-A (VEGF-A) in the decidual cells and vascular endothelial growth factor receptor 2 (VEGFR2) in decidual vascular endothelial cells were also tested. Exogenous recombinant human CXCL1 supported endothelial cell proliferation and migration, and this effect was blocked by CXCL1-neutralizing antibody or CXCR2 inhibitor SB265610. The tube formation of HUVEC-HTR8/SVneo co-culture system was significantly stimulated by CXCL1, but this effect was markedly abrogated once they were pretreated with CXCL1-neutralizing antibody or CXCR2 inhibitor SB265610. In addition, the level of vascular endothelial growth factor A (VEGF-A) expression in HUVEC cells was increased by CXCL1, and this level was suppressed by CXCL1-neutralizing antibody or CXCR2 inhibitor SB265610. In vivo, compared with Group A (n = 3), decidual angiogenesis was significantly reduced in Group B by CD34 immunostaining. But compared with Group B, decidual angiogenesis was significantly increased in Group C. In addition, the expression of VEGF-A and VEGFR2 was significantly increased after neutralizing of CXCL1 in Group B. In conclusions, CXCL1 may play essential roles in decidual angiogenesis during the first trimester, and this function may be mediated in part via altering VEGF-A expression.


Assuntos
Quimiocina CXCL1/metabolismo , Decídua/irrigação sanguínea , Neovascularização Fisiológica , Trofoblastos/citologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular , Proliferação de Células , Quimiocina CXCL1/genética , Decídua/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Gravidez , Primeiro Trimestre da Gravidez , Transdução de Sinais , Trofoblastos/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
16.
Clin Sci (Lond) ; 135(7): 865-884, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33769466

RESUMO

Biliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C-X-C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.


Assuntos
Atresia Biliar/patologia , Quimiocina CXCL1/metabolismo , Interleucina-8/metabolismo , Infiltração de Neutrófilos , Fator de Transcrição STAT3/metabolismo , Animais , Atresia Biliar/metabolismo , Quimiocina CXCL1/genética , Modelos Animais de Doenças , Células Epiteliais , Humanos , Lactente , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Rotavirus , Infecções por Rotavirus , Fator de Transcrição STAT3/genética
17.
Neoplasia ; 23(4): 375-390, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33784590

RESUMO

The tumor microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumorigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumor growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple-negative breast cancers and that it directly induces Cancer-associated fibroblasts phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g., CXCL1), cytokines (e.g., IL-6) and growth factors (e.g., PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteína Nodal/genética , Proteína Nodal/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/fisiologia , Actinas/metabolismo , Linhagem Celular Tumoral , Quimiocina CXCL1/metabolismo , Quimiotaxia/fisiologia , Feminino , Humanos , Interleucina-6/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Neoplasias de Mama Triplo Negativas/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33597297

RESUMO

Multiple sclerosis (MS) is a chronic neurological disease of the central nervous system driven by peripheral immune cell infiltration and glial activation. The pathological hallmark of MS is demyelination, and mounting evidence suggests neuronal damage in gray matter is a major contributor to disease irreversibility. While T cells are found in both gray and white matter of MS tissue, they are typically confined to the white matter of the most commonly used mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Here, we used a modified EAE mouse model (Type-B EAE) that displays severe neuronal damage to investigate the interplay between peripheral immune cells and glial cells in the event of neuronal damage. We show that CD4+ T cells migrate to the spinal cord gray matter, preferentially to ventral horns. Compared to CD4+ T cells in white matter, gray matter-infiltrated CD4+ T cells were mostly immobilized and interacted with neurons, which are behaviors associated with detrimental effects to normal neuronal function. T cell-specific deletion of CXCR2 significantly decreased CD4+ T cell infiltration into gray matter in Type-B EAE mice. Further, astrocyte-targeted deletion of TAK1 inhibited production of CXCR2 ligands such as CXCL1 in gray matter, successfully prevented T cell migration into spinal cord gray matter, and averted neuronal damage and motor dysfunction in Type-B EAE mice. This study identifies astrocyte chemokine production as a requisite for the invasion of CD4+T cell into the gray matter to induce neuronal damage.


Assuntos
Astrócitos/patologia , Linfócitos T CD4-Positivos/metabolismo , Substância Cinzenta/patologia , Esclerose Múltipla/patologia , Receptores de Interleucina-8B/metabolismo , Animais , Astrócitos/metabolismo , Linfócitos T CD4-Positivos/patologia , Quimiocina CXCL1/metabolismo , Quimiocina CXCL5/metabolismo , Quimiocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Feminino , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Corno Ventral da Medula Espinal/patologia , Imagem com Lapso de Tempo
19.
Cancer Sci ; 112(6): 2140-2157, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33609307

RESUMO

Non-small-cell lung cancer (NSCLC), with its aggressive biological behavior, is one of the most diagnosed cancers. Tumor-associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer, however the mechanisms involved are far from defined. In the present study, by developing an orthotopic NSCLC mouse model based on chronic inflammation, we proved that an inflammatory microenvironment accelerated the growth of orthotopic xenografts in vivo. Tumor-associated macrophages, the most abundant population of inflammatory cells, were identified. Treatment with macrophage-conditioned medium (MCM) promoted the growth and migration of NSCLC cells. Using bioinformatics analysis, we identified downregulated PP2Ac expression in NSCLC cells upon treatment with MCM. We further confirmed that this downregulation was executed in an NF-κB pathway-dependent manner. As IκB kinase (IKK) has been proved to be a substrate of PP2Ac, inhibition on PP2Ac could result in amplification of NF-κB pathway signaling. Overexpression of PP2Ac, or the dominant-negative forms of IKK or IκB, attenuated the acceleration of growth and metastasis by MCM. Using bioinformatics analysis, we further identified that CXCL1 and COL6A1 could be downstream of NF-κB/PP2Ac pathway. Luciferase assay and ChIP assay further confirmed the location of response elements on the promoter regions of CXCL1 and COL6A1. Elevated CXCL1 facilitated angiogenesis, whereas upregulated COL6A1 promoted proliferation and migration.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Proteína Fosfatase 2/metabolismo , Macrófagos Associados a Tumor/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Colágeno Tipo VI/genética , Colágeno Tipo VI/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Pessoa de Meia-Idade , Neovascularização Patológica , Proteína Fosfatase 2/genética , Transdução de Sinais
20.
J Invest Dermatol ; 141(7): 1772-1779.e6, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33548244

RESUMO

Psoriasis is a debilitating skin disease characterized by epidermal thickening, abnormal keratinocyte differentiation, and proinflammatory immune cell infiltrate into the affected skin. IL-17A plays a critical role in the etiology of psoriasis. ACT1, an intracellular adaptor protein and a putative ubiquitin E3 ligase, is essential for signal transduction downstream of the IL-17A receptor. Thus, IL-17A signaling in general, and ACT1 specifically, represent attractive targets for the treatment of psoriasis. We generated Act1 knockout and Act1 L286G knockin (ligase domain) mice to investigate the potential therapeutic effects of targeting ACT1 and its U-box domain, respectively. Act1 knockout, but not Act1 L286G knockin, mice were resistant to increases in CXCL1 plasma levels induced by subcutaneous injection of recombinant IL-17A. Moreover, in a mouse model of psoriasiform dermatitis induced by intradermal IL-23 injection, Act1 knockout, but not Act1 L286G knockin, was protective against increases in ear thickness, keratinocyte hyperproliferation, expression of genes for antimicrobial peptides and chemokines, and infiltration of monocytes and macrophages. Our studies highlight the critical contribution of ACT1 to proinflammatory skin changes mediated by the IL-23/IL-17 signaling axis and illustrate the need for further insight into ACT1 E3 ligase activity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Interleucina-23/imunologia , Psoríase/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Introdução de Genes , Humanos , Interleucina-17/administração & dosagem , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/administração & dosagem , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Knockout , Psoríase/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Transdução de Sinais/imunologia , Pele/imunologia , Pele/patologia
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