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

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date


Document Type



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

Journal/Book/Conference Title

Mucosal immunology

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Link to Article in PubMed

PubMed ID