RESUMO
Innate immunity is the body's first line of defense against infections. Innate immune cells express pattern recognition receptors in distinct cellular compartments that are responsible to detect either pathogens-associated molecules or cellular components derived from damaged cells, to trigger intracellular signaling pathways that lead to the activation of inflammatory responses. Inflammation is essential to coordinate immune cell recruitment, pathogen elimination and to keep normal tissue homeostasis. However, uncontrolled, misplaced or aberrant inflammatory responses could lead to tissue damage and drive chronic inflammatory diseases and autoimmunity. In this context, molecular mechanisms that tightly regulate the expression of molecules required for the signaling of innate immune receptors are crucial to prevent pathological immune responses. In this review, we discuss the ubiquitination process and its importance in the regulation of innate immune signaling and inflammation. Then, we summarize the roles of Smurf1, a protein that works on ubiquitination, on the regulation of innate immune signaling and antimicrobial mechanisms, emphasizing its substrates and highlighting its potential as a therapeutic target for infectious and inflammatory conditions.
Assuntos
Transdução de Sinais , Ubiquitina , Humanos , Ubiquitina/metabolismo , Imunidade Inata , Inflamação , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Previously we showed that 65-kDa Mycobacterium leprae heat shock protein (Hsp65) is a target for the development of a tuberculosis vaccine. Here we evaluated peripheral blood mononuclear cells (PBMC) from healthy individuals or tuberculosis patients stimulated with two forms of Hsp65 antigen, recombinant DNA that encodes Hsp65 (DNA-HSP65) or recombinant Hsp65 protein (rHsp65) in attempting to mimic a prophylactic or therapeutic study in vitro, respectively. Proliferation and cytokine-producing CD4+ or CD8+ cell were assessed by flow cytometry. The CD4+ cell proliferation from healthy individuals was stimulated by DNA-HSP65 and rHsp65, while CD8+ cell proliferation from healthy individuals or tuberculosis patients was stimulated by rHSP65. DNA-HSP65 did not improve the frequency of IFN-gamma+ cells from healthy individuals or tuberculosis patients. Furthermore, we found an increase in the frequency of IL-10-producing cells in both groups. These findings show that Hsp65 antigen activates human lymphocytes and plays an immune regulatory role that should be addressed as an additional antigen for the development of antigen-combined therapies.
Assuntos
Proteínas de Bactérias/imunologia , Chaperonina 60/imunologia , Imunidade Celular , Ativação Linfocitária , Tuberculose/imunologia , Adulto , Proteínas de Bactérias/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Chaperonina 60/genética , Citotoxicidade Imunológica , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Macrófagos Alveolares/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Proteínas Recombinantes/imunologia , Vacinas contra a Tuberculose/imunologia , Regulação para Cima , Vacinas de DNA/farmacologia , Adulto JovemRESUMO
Monocyte migration into tissues, an important event in inflammation, requires an intricate interplay between determinants on cell surfaces and extracellular matrix (ECM). Galectin-3 is able to modulate cell-ECM interactions and is an important mediator of inflammation. In this study, we sought to investigate whether interactions established between galectin-3 and ECM glycoproteins are involved in monocyte migration, given that the mechanisms by which monocytes move across the endothelium and through the extravascular tissue are poorly understood. Using the in vitro transwell system, we demonstrated that monocyte migration was potentiated in the presence of galectin-3 plus laminin or fibronectin, but not vitronectin, and was dependent on the carbohydrate recognition domain of the lectin. Only galectin-3-fibronectin combinations potentiated the migration of monocyte-derived macrophages. In binding assays, galectin-3 did not bind to fibronectin, whereas both the full-length and the truncated forms of the lectin, which retains carbohydrate binding ability, were able to bind to laminin. Our results show that monocytes migrate through distinct mechanisms and selective interactions with the extracellular matrix driven by galectin-3. We suggest that the lectin may bridge monocytes to laminin and may also activate these cells, resulting in the positive regulation of other adhesion molecules and cell adhesion to fibronectin.
RESUMO
CD4(+) Foxp3(+) regulatory T cells inhibit the production of interferon-γ, which is the major mediator of protection against Mycobacterium tuberculosis infection. In this study, we evaluated whether the protection conferred by three different vaccines against tuberculosis was associated with the number of spleen and lung regulatory T cells. We observed that after homologous immunization with the 65 000 molecular weight heat-shock protein (hsp 65) DNA vaccine, there was a significantly higher number of spleen CD4(+) Foxp3(+) cells compared with non-immunized mice. Heterologous immunization using bacillus Calmette-Guérin (BCG) to prime and DNA-hsp 65 to boost (BCG/DNA-hsp 65) or BCG to prime and culture filtrate proteins (CFP)-CpG to boost (BCG/CFP-CpG) induced a significantly higher ratio of spleen CD4(+) /CD4(+) Foxp3(+) cells compared with non-immunized mice. In addition, the protection conferred by either the BCG/DNA-hsp 65 or the BCG/CFP-CpG vaccines was significant compared with the DNA-hsp 65 vaccine. Despite the higher ratio of spleen CD4(+) /CD4(+) Foxp3(+) cells found in BCG/DNA-hsp 65-immunized or BCG/CFP-CpG-immunized mice, the lungs of both groups of mice were better preserved than those of DNA-hsp 65-immunized mice. These results confirm the protective efficacy of BCG/DNA-hsp 65 and BCG/CFP-CpG heterologous prime-boost vaccines and the DNA-hsp 65 homologous vaccine. Additionally, the prime-boost regimens assayed here represent a promising strategy for the development of new vaccines to protect against tuberculosis because they probably induce a proper ratio of CD4(+) and regulatory (CD4(+) Foxp3(+) ) cells during the immunization regimen. In this study, this ratio was associated with a reduced number of regulatory cells and no injury to the lungs.