Intramacrophage lipid accumulation compromises T cell responses and is associated with impaired drug therapy against visceral leishmaniasis

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Araújo, M (Author) Other; Moreira, D (Author) Other; Mesquita, I (Author) Other; Ferreira, C (Author) Other; Mendes Frias, A (Author) Other; Barros Carvalho, S (Author) Other; Dinis Oliveira, RJ (Author) Other; Duarte Oliveira, C (Author) Other; Cunha, C (Author) Other; Carvalho, A (Author) Other; Saha, B (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Estaquier, J (Author) Other; Silvestre, R (Author) Other

Journal

Title: Immunology

Vol. 170

Pages: 510-526

ISSN: 0019-2805

Publisher: Wiley-Blackwell

Indexing

Scopus - 0 Citations

Other information

Authenticus ID: P-00Z-0FP

DOI: 10.1111/imm.13686

Abstract (EN): <jats:title>Abstract</jats:title><jats:p>Under perturbing conditions such as infection with <jats:italic>Leishmania</jats:italic>, a protozoan parasite living within the phagosomes in mammalian macrophages, cellular and organellar structures, and metabolism are dynamically regulated for neutralizing the pressure of parasitism. However, how modulations of the host cell metabolic pathways support <jats:italic>Leishmania</jats:italic> infection remains unknown. Herein, we report that lipid accumulation heightens the susceptibility of mice to <jats:italic>L. donovani</jats:italic> infection and promotes resistance to first¿line anti¿leishmanial drugs. Despite being pro¿inflammatory, the in vitro generated uninfected lipid¿laden macrophages (LLMs) or adipose¿tissue macrophages (ATMs) display lower levels of reactive oxygen and nitrogen species. Upon infection, LLMs secrete higher IL¿10 and lower IL¿12p70 cytokines, inhibiting CD4<jats:sup>+</jats:sup> T cell activation and Th1 response suggesting a key modulatory role for intramacrophage lipid accumulation in anti¿leishmanial host defence. We, therefore, examined this causal relationship between lipids and immunomodulation using an in vivo high¿fat diet (HFD) mouse model. HFD increased the susceptibility to <jats:italic>L. donovani</jats:italic> infection accompanied by a defective CD4<jats:sup>+</jats:sup> Th1 and CD8<jats:sup>+</jats:sup> T cell response. The white adipose tissue of HFD mice displays increased susceptibility to <jats:italic>L. donovani</jats:italic> infection with the preferential infection of F4/80<jats:sup>+</jats:sup>CD11b<jats:sup>+</jats:sup>CD11c<jats:sup>+</jats:sup> macrophages with higher levels of neutral lipids reserve. The HFD increased resistance to a first¿line anti¿leishmanial drug associated with a defective adaptive immune response. These data demonstrate that the accumulation of neutral lipids contributes to susceptibility to visceral leishmaniasis hindering host¿protective immune response and reducing the efficacy of antiparasitic drug therapies.</jats:p>

Language: English

Type (Professor's evaluation): Scientific