RESUMO
CD43 (leukosialin) is a large sialoglycoprotein abundantly expressed on the surface of most cells from the hematopoietic lineage. CD43 is directly involved in the contact between cells participating in a series of events such as signaling, adherence and host parasite interactions. In this study we examined the role of CD43 in the immune response against Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, a potential life-threatening illness endemic in 21 Latin American countries according to the WHO. The acute stage of infection is marked by intense parasitemia and cardiac tissue parasitism, resulting in the recruitment of inflammatory cells and acute damage to the heart tissue. We show here that CD43-/- mice were more resistant to infection due to increased cytotoxicity of antigen specific CD8+ T cells and reduced inflammatory infiltration in the cardiac tissue, both contributing to lower cardiomyocyte damage. In addition, we demonstrate that the induction of acute myocarditis involves the engagement of CD43 cytoplasmic tripeptide sequence KRR to ezrin-radixin-moiesin cytoskeletal proteins. Together, our results show the participation of CD43 in different events involved in the pathogenesis of T. cruzi infection, contributing to a better overall understanding of the mechanisms underlying the pathogenesis of acute chagasic cardiomyopathy.
Assuntos
Doença de Chagas/metabolismo , Inflamação/patologia , Leucossialina/metabolismo , Miocárdio/patologia , Animais , Antígenos de Protozoários/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Doença de Chagas/imunologia , Doença de Chagas/patologia , Citotoxicidade Imunológica , Suscetibilidade a Doenças , Masculino , Camundongos Endogâmicos C57BL , Mutação/genética , Miocardite/imunologia , Miocardite/parasitologia , Miocardite/patologia , Parasitemia/imunologia , Fagócitos/patologia , Baço/imunologia , Análise de SobrevidaRESUMO
Tumors are formed by several cell types interacting in a complex environment of soluble and matrix molecules. The crosstalk between the cells and extracellular components control tumor fate. Macrophages are highly plastic and diverse immune cells that are known to be key regulators of this complex network, which is mostly because they can adjust their metabolism and reprogram their phenotype and effector function. Here, we review the studies that disclose the central role of metabolism and tumor microenvironment in shaping the phenotype and function of macrophages, highlighting the importance of the hexosamine biosynthetic pathway. We further discuss growing evidence of nutrient-sensitive protein modifications such as O-GlcNAcylation and extracellular glycosylation in the function and polarization of tumor-associated macrophages.
Assuntos
Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Animais , Glicosilação , Humanos , FenótipoRESUMO
Cancer cells depend on altered metabolism and nutrient uptake to generate and keep the malignant phenotype. The hexosamine biosynthetic pathway is a branch of glucose metabolism that produces UDP-GlcNAc and its derivatives, UDP-GalNAc and CMP-Neu5Ac and donor substrates used in the production of glycoproteins and glycolipids. Growing evidence demonstrates that alteration of the pool of activated substrates might lead to different glycosylation and cell signaling. It is already well established that aberrant glycosylation can modulate tumor growth and malignant transformation in different cancer types. Therefore, biosynthetic machinery involved in the assembly of aberrant glycans are becoming prominent targets for anti-tumor drugs. This review describes three classes of glycosylation, O-GlcNAcylation, N-linked, and mucin type O-linked glycosylation, involved in tumor progression, their biosynthesis and highlights the available inhibitors as potential anti-tumor drugs.
RESUMO
Induced pluripotent stem (iPS) cells are somatic cells that have been reprogrammed to a pluripotent state via the introduction of defined transcription factors. Although iPS is a potentially valuable resource for regenerative medicine and drug development, several issues regarding their pluripotency, differentiation propensity and potential for tumorigenesis remain to be elucidated. Analysis of cell surface glycans has arisen as an interesting tool for the characterization of iPS. An appropriate characterization of glycan surface molecules of human embryonic stem (hES) cells and iPS cells might generate crucial data to highlight their role in the acquisition and maintenance of pluripotency. In this study, we characterized the surface glycans of iPS generated from menstrual blood-derived mesenchymal cells (iPS-MBMC). We demonstrated that, upon spontaneous differentiation, iPS-MBMC present high amounts of terminal ß-galactopyranoside residues, pointing to an important role of terminal-linked sialic acids in pluripotency maintenance. The removal of sialic acids by neuraminidase induces iPS-MBMC and hES cells differentiation, prompting an ectoderm commitment. Exposed ß-galactopyranose residues might be recognized by carbohydrate-binding molecules found on the cell surface, which could modulate intercellular or intracellular interactions. Together, our results point for the first time to the involvement of the presence of terminal sialic acid in the maintenance of embryonic stem cell pluripotency and, therefore, the modulation of sialic acid biosynthesis emerges as a mechanism that may govern stem cell differentiation.