TAK1 Deficiency in Macrophages Increases Host Susceptibility to Leishmania Infection

Abstract

Abstract Leishmania parasites mainly infect macrophages and may cause severe immunopathologies in their host, which are called leishmaniases. In the current work, we infected human and mouse macrophages in vitro with Leishmania major, an etiological agent of cutaneous leishmaniasis, and found that inhibition or deletion of the transforming growth factor β–activated kinase 1 (TAK1) gene resulted in increased parasite loads. In vivo, following a challenge with L. major, mice with a macrophage-specific deletion of TAK1 showed increased clinical signs and higher parasite loads compared with wild-type controls. TAK1 deficiency in mouse macrophages led to biased Th2 cell responses during the acute stage of infection, characterized by a decrease in interferon-γ expression, and increased expression of IL-4, IL-5 and IL-10. Finally, we found that, in the late stage of L. major infection, excessive Th2-related cytokines led to high arginase 1 expression in mouse tissues and a significant reduction of NO production both locally and systemically, resulting in compromised control of Leishmania. These findings suggest that TAK1 plays a vital role in host resistance to Leishmania infection.