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
Department of Medicine, Division of Infectious Diseases and Immunology
Hemic and Immune Systems | Immunology and Infectious Disease | Parasitic Diseases | Pathological Conditions, Signs and Symptoms | Respiratory Tract Diseases
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-gamma. 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-gamma. 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-alpha/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-gamma primarily by CD8(+) T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model.
DOI of Published Version
Mucosal Immunol. 2019 Mar;12(2):312-322. doi: 10.1038/s41385-018-0093-5. Epub 2018 Oct 18. Link to article on publisher's site
Galvao-Filho B, de Castro JT, Figueiredo MM, Rosmaninho CG, Antonelli L, Gazzinelli RT. (2019). 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. Open Access Publications by UMass Chan Authors. https://doi.org/10.1038/s41385-018-0093-5. Retrieved from https://escholarship.umassmed.edu/oapubs/3805