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2035-01-01
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THE EMERGENCE OF PATHOGENIC TNF/INOS PRODUCING DENDRITIC CELLS (TIP-DCS) IN A MALARIA MODEL OF ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS DEPENDENT ON CCR4
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Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brazil / Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil / University of Massachusetts Medical School. Department of Medicine. Worcester, MA, USA / Fundação Oswaldo Cruz. Fiocruz SP. Plataforma de Medicinal Translacional. São Paulo, SP, Brazil / Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Ribeirão Preto, SP, Brasil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil / University of Massachusetts Medical School. Department of Medicine. Worcester, MA, USA / Fundação Oswaldo Cruz. Fiocruz SP. Plataforma de Medicinal Translacional. São Paulo, SP, Brazil / Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Ribeirão Preto, SP, Brasil.
Abstract
Malaria-associated acute respiratory distress syndrome (MA-ARDS) and acute lung injury (ALI) are complications that cause lung damage and often leads to death. The MA-ARDS/ALI is associated with a Type 1 inflammatory response mediated by T lymphocytes and IFN-γ. Here, we used the Plasmodium berghei NK65 (PbN)-induced MA-ALI/ARDS model that resembles human disease and confirmed that lung CD4+ and CD8+ T cells predominantly expressed Tbet and IFN-γ. Surprisingly, we found that development of MA-ALI/ARDS was dependent on functional CCR4, known to mediate the recruitment of Th2 lymphocytes and regulatory T cells. However, in this Type 1 inflammation-ARDS model, CCR4 was not involved in the recruitment of T lymphocytes, but was required for the emergence of TNF-α/iNOS producing dendritic cells (Tip-DCs) in the lungs. In contrast, recruitment of Tip-DCs and development of MA-ALI/ARDS were not altered in CCR2-/- mice. Importantly, we showed that NOS2-/- mice are resistant to PbN-induced lung damage, indicating that reactive nitrogen species produced by Tip-DCs play an essential role in inducing MA-ARDS/ALI. Lastly, our experiments suggest that production of IFN-γ primarily by CD8+ T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model.
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