3d-hepatocyte culture applied to parasitology: immune activation of canine hepatic spheroids exposed to leishmania infantum

Armanda V. Rodrigues, Graça Alexandre-Pires, Ana Valério-Bolas, David Santos-Mateus, Mariana Rafael-Fernandes, Maria A. Pereira, Dário Ligeiro, Telmo Nunes, Raquel Alves-Azevedo, Marcos Santos, Isabel Pereira da Fonseca, Gabriela Santos-Gomes

Research output: Contribution to journalArticlepeer-review

Abstract

The application of innovative three-dimensional (3D) spheroids cell culture strategy to Parasitology offers the opportunity to closely explore host–parasite interactions. Here we present a first report on the application of 3D hepatic spheroids to unravel the immune response of canine hepatocytes exposed to Leishmania infantum. The liver, usually considered a major metabolic organ, also performs several important immunological functions and constitutes a target organ for L. infantum infection, the etiological agent of canine leishmaniasis (CanL), and a parasitic disease of major veterinary and public health concern. 3D hepatic spheroids were able to sense and immunologically react to L. infantum parasites, generating an innate immune response by increasing nitric oxide (NO) production and enhancing toll-like receptor (TLR) 2 and interleukin-10 gene expression. The immune response orchestrated by canine hepatocytes also lead to the impairment of several cytochrome P450 (CYP450) with possible implications for liver natural xenobiotic metabolization capacity. The application of meglumine antimoniate (MgA) increased the inflammatory response of 3D hepatic spheroids by inducing the expression of Nucleotide oligomerization domain (NOD)-like receptors 1 and NOD2 and TLR2, TLR4, and TLR9 and enhancing gene expression of tumour necrosis factor α. It is therefore suggested that hepatocytes are key effector cells and can activate and orchestrate the immune response to L. infantum parasites.

Original languageEnglish
Article number628
Pages (from-to)628-649
Number of pages21
JournalBiomedicines
Volume8
Issue number12
DOIs
Publication statusPublished - 18 Dec 2020

Keywords

  • 3D cell culture
  • Hepatocytes
  • Immune response
  • Leishmania infantum
  • Meglumine antimoniate

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