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1.
J Immunol ; 207(4): 1200-1210, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321227

RESUMO

Esophagogastric adenocarcinomas (EAC) are obesity-associated malignancies underpinned by severe immune dysregulation and inflammation. Our previous work indicates that NK cells migrate to EAC omentum, where they undergo phenotypic and functional alterations and apoptosis. In this study, we investigate whether such erroneous chemotaxis to omentum is paralleled by compromised NK cell infiltration of EAC patient tumor and examine the role of the inflammatory chemokine fractalkine in shaping the NK cell-mediated response. Our data show diminished NK cell frequencies in EAC tumor compared with those in the circulation and reveal that intratumoral NK cell frequencies decline as visceral obesity increases in EAC patients. Our in vitro findings demonstrate that antagonism of fractalkine receptor CX3CR1 significantly reduces NK cell migration to EAC patient-derived, omental adipose tissue-conditioned media, but not toward tumor-conditioned media. These data suggest fractalkine is a key driver of NK cell chemotaxis to omentum but has a lesser role in NK cell homing to tumor in EAC. We propose that this may offer a novel therapeutic strategy to limit NK cell depletion in the omentum of obese EAC patients, and our data suggest the optimal timing for CX3CR1 antagonism is after neoadjuvant chemoradiotherapy. Our functional studies demonstrate that fractalkine induces the conversion from CX3CR1+CD27- to CX3CR1-CD27+ NK cells and increases their IFN-γ and TNF-α production, indicative of its role in shaping the dominant NK cell phenotype in EAC omentum. This study uncovers crucial and potentially druggable pathways underpinning NK cell dysfunction in obesity-associated cancer and provides compelling insights into fractalkine's diverse biological functions.


Assuntos
Quimiocina CX3CL1/imunologia , Quimiotaxia/imunologia , Células Matadoras Naturais/imunologia , Obesidade/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Adenocarcinoma/imunologia , Tecido Adiposo/imunologia , Movimento Celular/imunologia , Neoplasias Esofágicas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores de Quimiocinas/imunologia , Neoplasias Gástricas/imunologia
2.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206505

RESUMO

Myosins are a remarkable superfamily of actin-based motor proteins that use the energy derived from ATP hydrolysis to translocate actin filaments and to produce force. Myosins are abundant in different types of tissues and involved in a large variety of cellular functions. Several classes of the myosin superfamily are expressed in the nervous system; among them, non-muscle myosin II (NM II) is expressed in both neurons and non-neuronal brain cells, such as astrocytes, oligodendrocytes, endothelial cells, and microglia. In the nervous system, NM II modulates a variety of functions, such as vesicle transport, phagocytosis, cell migration, cell adhesion and morphology, secretion, transcription, and cytokinesis, as well as playing key roles during brain development, inflammation, repair, and myelination functions. In this review, we will provide a brief overview of recent emerging roles of NM II in resting and activated microglia cells, the principal regulators of immune processes in the central nervous system (CNS) in both physiological and pathological conditions. When stimulated, microglial cells react and produce a number of mediators, such as pro-inflammatory cytokines, free radicals, and nitric oxide, that enhance inflammation and contribute to neurodegenerative diseases. Inhibition of NM II could be a new therapeutic target to treat or to prevent CNS diseases.


Assuntos
Microglia/metabolismo , Miosina Tipo II/metabolismo , Animais , Biomarcadores , Movimento Celular/imunologia , Citoesqueleto/metabolismo , Humanos , Microglia/imunologia , Fagocitose/imunologia
3.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204207

RESUMO

ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract. The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood. This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA. In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed. Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures. Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells. Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/etiologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Suscetibilidade a Doenças , Granulomatose com Poliangiite/etiologia , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade , Biomarcadores , Movimento Celular/imunologia , Gerenciamento Clínico , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/metabolismo , Granulomatose com Poliangiite/terapia , Humanos , Imunidade Inata , Imuno-Histoquímica/métodos , Especificidade de Órgãos/imunologia
4.
Theranostics ; 11(14): 7072-7091, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093872

RESUMO

Simultaneous targeting of both the tumor microenvironment and cancer cells by a single nanomedicine has not been reported to date. Here, we report the dual properties of zero-valent-iron nanoparticle (ZVI-NP) to induce cancer-specific cytotoxicity and anti-cancer immunity. Methods: Cancer-specific cytotoxicity induced by ZVI-NP was determined by MTT assay. Mitochondria functional assay, immunofluorescence staining, Western blot, RT-qPCR, and ChIP-qPCR assays were used to dissect the mechanism underlying ZVI-NP-induced ferroptotic cancer cell death. The therapeutic potential of ZVI-NP was evaluated in immunocompetent mice and humanized mice. Immune cell profiles of allografts and ex vivo cultured immune cells were examined by flow cytometry analysis, RT-qPCR assay, and immunofluorescence. Results: ZVI-NP caused mitochondria dysfunction, intracellular oxidative stress, and lipid peroxidation, leading to ferroptotic death of lung cancer cells. Degradation of NRF2 by GSK3/ß-TrCP through AMPK/mTOR activation was enhanced in such cancer-specific ferroptosis. In addition, ZVI-NP attenuated self-renewal ability of cancer and downregulated angiogenesis-related genes. Importantly, ZVI-NP augmented anti-tumor immunity by shifting pro-tumor M2 macrophages to anti-tumor M1, decreasing the population of regulatory T cells, downregulating PD-1 and CTLA4 in CD8+ T cells to potentiate their cytolytic activity against cancer cells, while attenuating PD-L1 expression in cancer cells in vitro and in tumor-bearing immunocompetent mice. In particular, ZVI-NPs preferentially accumulated in tumor and lung tissues, leading to prominent suppression of tumor growth and metastasis. Conclusions: This dual-functional nanomedicine established an effective strategy to synergistically induce ferroptotic cancer cell death and reprogram the immunosuppressive microenvironment, which highlights the potential of ZVI-NP as an advanced integrated anti-cancer strategy.


Assuntos
Ferroptose/efeitos dos fármacos , Ferro/farmacologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Fator 2 Relacionado a NF-E2/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Aloenxertos , Animais , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Imunoprecipitação da Cromatina , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/imunologia
5.
Adv Protein Chem Struct Biol ; 126: 63-90, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34090620

RESUMO

Cancer is one of the leading causes of mortality in the world. The conventional treatment strategies of cancer are surgery, radiation, and chemotherapy. However, in the advanced stage of the disease chemotherapy is the prime treatment and it is effective in only less than 10% of the patients. Therefore, there is an urgent need to find out novel therapeutic targets and delineate the mechanism of action of these targets for better management of this disease. Recent studies have shown that some of the proteins have differential role in different cancers. Therefore, it is pertinent that the targeting of these proteins should be based on the type of cancer. The nuclear receptor, FXR, is one of the vital proteins that regulate cell apoptosis. Besides, it also regulates other processes such as cell proliferation, angiogenesis, invasion, and migration. Studies suggest that the low or high expression of FXR is associated with the progression of carcinogenesis depending on the cancer types. Due to the diverse expression, it functions as both tumor suppressor and promoter. Previous studies suggest the overexpression of FXR in breast, lung, esophageal, and prostate cancer, which is related to poor survival and poor prognosis in patients. Therefore, targeting FXR with agonists and antagonists play different outcome in different cancers. Hence, this review describes the role of FXR in different cancers and the role of its inhibitors and activators for the prevention and treatment of various cancers.


Assuntos
Apoptose/imunologia , Carcinogênese/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Receptores Citoplasmáticos e Nucleares/imunologia , Animais , Carcinogênese/patologia , Movimento Celular/imunologia , Proliferação de Células , Humanos , Invasividade Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/diagnóstico , Neoplasias/terapia , Neovascularização Patológica/diagnóstico , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Neovascularização Patológica/terapia
6.
Hematol Oncol ; 39 Suppl 1: 15-23, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105821

RESUMO

Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.


Assuntos
Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Dendríticas , Histiocitose de Células de Langerhans , Medicina de Precisão , Linfócitos T , Substituição de Aminoácidos , Diferenciação Celular/genética , Movimento Celular/genética , Células Dendríticas/imunologia , Células Dendríticas/patologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
7.
Front Immunol ; 12: 597595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953706

RESUMO

The rapid response of neutrophils throughout the body to a systemic challenge is a critical first step in resolution of bacterial infection such as Escherichia coli (E. coli). Here we delineated the dynamics of this response, revealing novel insights into the molecular mechanisms using lung and spleen intravital microscopy and 3D ex vivo culture of living precision cut splenic slices in combination with fluorescent labelling of endogenous leukocytes. Within seconds after challenge, intravascular marginated neutrophils and lung endothelial cells (ECs) work cooperatively to capture pathogens. Neutrophils retained on lung ECs slow their velocity and aggregate in clusters that enlarge as circulating neutrophils carrying E. coli stop within the microvasculature. The absolute number of splenic neutrophils does not change following challenge; however, neutrophils increase their velocity, migrate to the marginal zone (MZ) and form clusters. Irrespective of their location all neutrophils capturing heat-inactivated E. coli take on an activated phenotype showing increasing surface CD11b. At a molecular level we show that neutralization of ICAM-1 results in splenic neutrophil redistribution to the MZ under homeostasis. Following challenge, splenic levels of CXCL12 and ICAM-1 are reduced allowing neutrophils to migrate to the MZ in a CD29-integrin dependent manner, where the enlargement of splenic neutrophil clusters is CXCR2-CXCL2 dependent. We show directly molecular mechanisms that allow tissue resident neutrophils to provide the first lines of antimicrobial defense by capturing circulating E. coli and forming clusters both in the microvessels of the lung and in the parenchyma of the spleen.


Assuntos
Movimento Celular/imunologia , Infecções por Escherichia coli/imunologia , Escherichia coli/imunologia , Pulmão/imunologia , Neutrófilos/imunologia , Baço/imunologia , Animais , Quimiocina CXCL12/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Infecções por Escherichia coli/patologia , Feminino , Molécula 1 de Adesão Intercelular/imunologia , Pulmão/patologia , Camundongos , Neutrófilos/patologia , Baço/patologia
8.
Nat Commun ; 12(1): 3010, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021148

RESUMO

Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Memória Imunológica/imunologia , Pulmão/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/virologia , Movimento Celular/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/virologia , SARS-CoV-2/fisiologia , Linfócitos T/metabolismo
9.
Immunity ; 54(6): 1219-1230.e7, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915109

RESUMO

The sympathetic nervous system (SNS) controls various physiological functions via the neurotransmitter noradrenaline. Activation of the SNS in response to psychological or physical stress is frequently associated with weakened immunity. Here, we investigated how adrenoceptor signaling influences leukocyte behavior. Intravital two-photon imaging after injection of noradrenaline revealed transient inhibition of CD8+ and CD4+ T cell locomotion in tissues. Expression of ß-adrenergic receptor in hematopoietic cells was not required for NA-mediated inhibition of motility. Rather, chemogenetic activation of the SNS or treatment with adrenergic receptor agonists induced vasoconstriction and decreased local blood flow, resulting in abrupt hypoxia that triggered rapid calcium signaling in leukocytes and halted cell motility. Oxygen supplementation reversed these effects. Treatment with adrenergic receptor agonists impaired T cell responses induced in response to viral and parasitic infections, as well as anti-tumor responses. Thus, stimulation of the SNS impairs leukocyte mobility, providing a mechanistic understanding of the link between adrenergic receptors and compromised immunity.


Assuntos
Adrenérgicos/imunologia , Movimento Celular/imunologia , Imunidade/imunologia , Leucócitos/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Sinalização do Cálcio/imunologia , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
10.
Immunity ; 54(5): 859-874, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33838745

RESUMO

Chemokines are chemotactic cytokines that regulate the migration of immune cells. Chemokines function as cues for the coordinated recruitment of immune cells into and out of tissue and also guide the spatial organization and cellular interactions of immune cells within tissues. Chemokines are critical in directing immune cell migration necessary to mount and then deliver an effective anti-tumor immune response; however, chemokines also participate in the generation and recruitment of immune cells that contribute to a pro-tumorigenic microenvironment. Here, we review the role of the chemokine system in anti-tumor and pro-tumor immune responses and discuss how malignant cells and the tumor microenvironment regulate the overall chemokine landscape to shape the type and outcome of immune responses to cancer and cancer treatment.


Assuntos
Quimiocinas/imunologia , Imunidade/imunologia , Neoplasias/imunologia , Animais , Carcinogênese/imunologia , Movimento Celular/imunologia , Humanos , Microambiente Tumoral/imunologia
11.
Am J Clin Dermatol ; 22(3): 315-327, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33871811

RESUMO

Since the US Food and Drug Administration (FDA) approved tretinoin in 1971, retinoids alone or combined with other agents have become the mainstay of acne treatment. Retinoids act through binding to retinoic acid receptors, altering expression levels of hundreds of cellular proteins affecting multiple pathways involved in acne pathogenesis. Retinoids have evolved from first-generation agents, such as tretinoin, through chemical modifications resulting in a second generation (etretinate and acitretin for psoriasis), a third generation (adapalene and tazarotene) and, most recently, a fourth (trifarotene). For all topical retinoids, local irritation has been associated with poor tolerability and suboptimal adherence. Efforts to improve tolerability have utilized novel delivery systems and/or novel agents. This qualitative literature review summarizes the evolution of the four topical single-agent retinoids available for the treatment of acne in the US today and their various formulations, presenting the rationale behind their development and data from key studies.


Assuntos
Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Retinoides/administração & dosagem , Acne Vulgar/imunologia , Administração Cutânea , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Fármacos Dermatológicos/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Receptores do Ácido Retinoico/metabolismo , Retinoides/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo , Resultado do Tratamento
12.
Aging (Albany NY) ; 13(8): 12239-12257, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33872218

RESUMO

Endothelial dysfunction, and the differentiation of smooth muscle cells (SMCs) into proliferative, secretory phenotypes, are two major pathophysiological processes in atherosclerosis. SMCs have the potential to recruit macrophages in atherosclerotic plaques, in which macrophages drive inflammatory responses. In this study, we found that microRNA-503-5p (miR-503-5p) was enriched in either extracellular vesicles (EVs), secreted by oxidized low-density lipoprotein-treated macrophages, or the EVs from peripheral blood mononuclear cells of atherosclerosis patients. miR-503-5p was transferred intercellularly from macrophages to the co-cultured human coronary artery endothelial cells (HCAECs) and HCASMCs via EVs, thus reducing the proliferative and angiogenic abilities of HCAECs and accelerating the proliferative and migrating abilities of HCASMCs. Smad family members 1, 2 and 7 were negatively regulated by miR-503-5p in HCAECs and HCASMCs. miR-503-5p was verified as an enhancer of inflammatory cytokines and adhesion molecules released by macrophages, in part via the down-regulation of smad family members 1, 2 and 7. The inhibition of miR-503-5p by lentivirus reduced atherosclerotic lesion formations in the aorta of atherosclerotic mice. Our work demonstrated a miR-503-5p- and EV-mediated mechanism for macrophage communication with HCAECs and HCASMCs in atherosclerosis. miR-503-5p is pro-atherosclerotic stimuli that may be a therapeutic target for atherosclerosis treatment.


Assuntos
Aterosclerose/imunologia , Comunicação Celular/genética , Vesículas Extracelulares/metabolismo , Macrófagos/imunologia , MicroRNAs/metabolismo , Adulto , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Comunicação Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Proliferação de Células/genética , Técnicas de Cocultura , Vasos Coronários/citologia , Vasos Coronários/patologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Lipoproteínas LDL/imunologia , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Miócitos de Músculo Liso , Cultura Primária de Células , Células RAW 264.7 , Células THP-1
13.
Aging (Albany NY) ; 13(8): 12143-12159, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902006

RESUMO

Increased accumulation of advanced glycation end products (AGEs) in diabetic skin is closely related to delayed wound healing. Studies have shown that the concentration of AGEs is elevated in the skin tissues and not subcutaneous tissues in refractory diabetic wounds, which suggests there may be a causal relationship between the two. In the present study, in vitro experiments revealed that AGEs activated neutrophils, and the migratory and adhesive functions of neutrophils decreased once AGE levels reached a certain threshold. Different levels of AGE expression differentially affected the function of neutrophils. Messenger RNA (mRNA) sequencing analysis combined with real-time polymerase chain reaction (PCR) showed that poliovirus receptor (PVR/CD155) and CTNND1, which play a role in migration- and adhesion-related signaling pathways, were decreased following AGE stimulation. Consequently, neutrophils cannot effectively stimulate the formation of the inflammatory belt needed to remove necrotic tissues and defend against foreign microorganisms within diabetic chronic wounds. In addition, this phenomenon may be related to the differential accumulation of AGEs in different layers of the skin.


Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus Experimental/complicações , Produtos Finais de Glicação Avançada/metabolismo , Neutrófilos/imunologia , Pele/patologia , Animais , Cateninas/metabolismo , Agregação Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Humanos , Masculino , Ratos , Receptores Virais/metabolismo , Pele/citologia , Pele/imunologia , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Cicatrização/imunologia
14.
Front Immunol ; 12: 609029, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868229

RESUMO

Due to its richness in antigen presenting cells, e.g., dendritic cells (DC), the skin has been identified as a promising route for immunotherapy and vaccination. Several years ago, a skin delivery system was developed based on epicutaneous patches allowing the administration of antigen through intact skin. Using mouse models, we have shown that epicutaneous allergen application leads to a rapid uptake and transport of allergen-positive cells to skin-draining lymph nodes (LN). This occurred primarily in animals previously sensitized to the same allergen. In that context, we sought to better understand the role of the specific preexisting immunity in allergen capture by skin DC and their subsequent migration to LN. Specifically, we investigated the role of humoral immunity induced by sensitization and the involvement of IgG Fc receptors (FcγR). Epicutaneous patches containing fluorescently-labeled ovalbumin (OVA) were applied to naïve mice that had previously received either sera or purified IgG isolated from OVA-sensitized mice. To investigate the involvement of FcγR, animals received 2.4G2 (anti-FcγRII/RIII) blocking antibody, 24 hours before patch application. Mice that received sera or purified IgG originating from OVA-sensitized mice showed an increase in the quantity of OVA-positive DC in skin and LN. Moreover, the blockade of FcγR reduced the number of OVA-positive DC in LN to a level similar to that observed in naïve animals. Overall, these results demonstrate that preexisting specific-IgG antibodies are involved in allergen capture by skin DC following EPIT through the involvement of antigen-specific IgG-FcγR.


Assuntos
Alérgenos/imunologia , Movimento Celular/imunologia , Imunidade Humoral , Células de Langerhans/imunologia , Linfonodos/imunologia , Alérgenos/administração & dosagem , Animais , Biomarcadores , Modelos Animais de Doenças , Hipersensibilidade/imunologia , Hipersensibilidade/terapia , Imunização , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Imunofenotipagem , Células de Langerhans/metabolismo , Linfonodos/metabolismo , Camundongos , Receptores Fc/metabolismo
15.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805762

RESUMO

Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX's effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.


Assuntos
Linfócitos B/patologia , Encefalomielite Autoimune Experimental/patologia , Toxina Pertussis/administração & dosagem , Células Th17/patologia , Transferência Adotiva/métodos , Animais , Linfócitos B/imunologia , Movimento Celular/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Índice de Gravidade de Doença , Células Th17/imunologia , Células Th17/transplante
16.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800359

RESUMO

Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics.


Assuntos
Doenças Cardiovasculares , Movimento Celular/imunologia , Fibrinólise/imunologia , Proteínas de Neoplasias , Neoplasias , Inibidor 1 de Ativador de Plasminogênio , Proteólise , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Fibrose , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Inibidor 1 de Ativador de Plasminogênio/imunologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/imunologia , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
17.
Int J Mol Sci ; 22(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917390

RESUMO

Glycosphingolipids (GSLs) are composed of a mono-, di-, or oligosaccharide and a ceramide and function as constituents of cell membranes. Various molecular species of GSLs have been identified in mammalian cells due to differences in the structures of oligosaccharides. The oligosaccharide structure can vary depending on cell lineage, differentiation stage, and pathology; this property can be used as a cell identification marker. Furthermore, GSLs are involved in various aspects of the immune response, such as cytokine production, immune signaling, migration of immune cells, and antibody production. GSLs containing certain structures exhibit strong immunogenicity in immunized animals and promote the production of anti-GSL antibodies. By exploiting this property, it is possible to generate antibodies that recognize the fine oligosaccharide structure of specific GSLs or glycoproteins. In our study using artificially synthesized GSLs (artGSLs), we found that several structural features are correlated with the antibody-inducing activity of GSLs. Based on these findings, we designed artGSLs that efficiently induce the production of antibodies accompanied by class switching and developed several antibodies that recognize not only certain glycan structures of GSLs but also those of glycoproteins. This review comprehensively introduces the immune activities of GSLs and their application as pharmaceuticals.


Assuntos
Anticorpos/imunologia , Formação de Anticorpos , Movimento Celular , Glicoesfingolipídeos/farmacologia , Switching de Imunoglobulina/efeitos dos fármacos , Transdução de Sinais , Animais , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Citocinas/imunologia , Glicoesfingolipídeos/química , Glicoesfingolipídeos/imunologia , Humanos , Transdução de Sinais/imunologia
18.
Immunity ; 54(5): 1037-1054.e7, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33756102

RESUMO

Immune cells identify and destroy tumors by recognizing cellular traits indicative of oncogenic transformation. In this study, we found that myocardin-related transcription factors (MRTFs), which promote migration and metastatic invasion, also sensitize cancer cells to the immune system. Melanoma and breast cancer cells with high MRTF expression were selectively eliminated by cytotoxic lymphocytes in mouse models of metastasis. This immunosurveillance phenotype was further enhanced by treatment with immune checkpoint blockade (ICB) antibodies. We also observed that high MRTF signaling in human melanoma is associated with ICB efficacy in patients. Using biophysical and functional assays, we showed that MRTF overexpression rigidified the filamentous actin cytoskeleton and that this mechanical change rendered mouse and human cancer cells more vulnerable to cytotoxic T lymphocytes and natural killer cells. Collectively, these results suggest that immunosurveillance has a mechanical dimension, which we call mechanosurveillance, that is particularly relevant for the targeting of metastatic disease.


Assuntos
Linfócitos/imunologia , Neoplasias/imunologia , Citoesqueleto de Actina/imunologia , Actinas/imunologia , Animais , Comunicação Celular/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/imunologia , Feminino , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia , Fatores de Transcrição/imunologia
19.
Front Immunol ; 12: 615477, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692789

RESUMO

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological "actinopathies" primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.


Assuntos
Movimento Celular , Leucócitos/metabolismo , Doenças da Imunodeficiência Primária/etiologia , Doenças da Imunodeficiência Primária/metabolismo , Fator de Resposta Sérica/metabolismo , Transativadores/metabolismo , Animais , Biomarcadores , Adesão Celular , Movimento Celular/genética , Movimento Celular/imunologia , Suscetibilidade a Doenças/imunologia , Humanos , Leucócitos/imunologia , Doenças da Imunodeficiência Primária/diagnóstico , Fator de Resposta Sérica/genética , Transdução de Sinais , Transativadores/genética
20.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669065

RESUMO

Immunosenescence is characterized by age-associated changes in immunological functions. Although age- and autoimmune-related sialadenitis cause dry mouth (xerostomia), the roles of immunosenescence and cellular senescence in the pathogenesis of sialadenitis remain unknown. We demonstrated that acquired immune cells rather than innate immune cells infiltrated the salivary glands (SG) of aged mice. An analysis of isolated epithelial cells from SG revealed that the expression levels of the chemokine CXCL13 were elevated in aged mice. Senescence-associated T cells (SA-Ts), which secrete large amounts of atypical pro-inflammatory cytokines, are involved in the pathogenesis of metabolic disorders and autoimmune diseases. The present results showed that SA-Ts and B cells, which express the CXCL13 receptor CXCR5, accumulated in the SG of aged mice, particularly females. CD4+ T cells derived from aged mice exhibited stronger in vitro migratory activity toward CXCL13 than those from young mice. In a mouse model of Sjögren's syndrome (SS), SA-Ts also accumulated in SG, presumably via CXCL12-CXCR4 signaling. Collectively, the present results indicate that SA-Ts accumulate in SG, contribute to the pathogenesis of age- and SS-related sialadenitis by up-regulating chemokines in epithelial cells, and have potential as therapeutic targets for the treatment of xerostomia caused by these types of sialadenitis.


Assuntos
Senescência Celular/imunologia , Quimiocinas/metabolismo , Células Epiteliais/metabolismo , Glândulas Salivares/metabolismo , Sialadenite/metabolismo , Síndrome de Sjogren/imunologia , Linfócitos T/metabolismo , Xerostomia/metabolismo , Animais , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular/imunologia , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Quimiocinas/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Glândulas Salivares/citologia , Glândulas Salivares/imunologia , Sialadenite/patologia , Síndrome de Sjogren/patologia , Linfócitos T/imunologia , Xerostomia/patologia
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