Sphingosine-1-phosphate signaling in Leishmania donovani infection in macrophages

PLoS Negl Trop Dis. 2018 Aug 17;12(8):e0006647. doi: 10.1371/journal.pntd.0006647. eCollection 2018 Aug.

Abstract

Background: Sphingosine-1-phosphate (S1P) is a crucial regulator of a wide array of cellular processes, such as apoptosis, cell proliferation, migration, and differentiation, but its role in Leishmania donovani infection is unknown.

Methodology/ principal findings: In the present study, we observed that L. donovani infection in THP-1 derived macrophages (TDM) leads to decrease in the expression of S1pr2 and S1pr3 at mRNA level. We further observed that Leishmania infection inhibits the phosphorylation of sphingosine kinase 1 (sphK1) in a time-dependent manner. Exogenous S1P supplementation decreases L. donovani induced ERK1/2 phosphorylation and increases p38 phosphorylation in TDM, resulting in a decrease in the intracellular parasite burden in a dose-dependent manner. On the other hand, sphK inhibition by DMS increases ERK1/2 phosphorylation leading to increased IL-10 and parasite load. To gain further insight, cytokines expression were checked in S1P supplemented TDM and we observed increase in IL-12, while decrease IL-10 expression at mRNA and protein levels. In addition, treatment of antagonist of S1PR2 and S1PR3 such as JTE-013 and CAY10444 respectively enhanced Leishmania-induced ERK1/2 phosphorylation and parasite load.

Conclusions: Our overall study not only reports the significant role of S1P signaling during L. donovani infection but also provides a novel platform for the development of new drugs against Leishmaniasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / genetics
  • Cytokines / metabolism
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation
  • Leishmania donovani / physiology*
  • Lysophospholipids / genetics
  • Lysophospholipids / metabolism*
  • Macrophages / metabolism
  • Macrophages / parasitology*
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / genetics
  • Sphingosine / metabolism

Substances

  • Cytokines
  • Lysophospholipids
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Extracellular Signal-Regulated MAP Kinases
  • Sphingosine

Grants and funding

Authors are thankful to Science and Engineering Research Board(SERB), Department of Science and Technology, New Delhi-110025 (http://www.serb.gov.in/home.php), Govt of India for supporting this work through Young Scientist Grant (SB/FT/LS-318/2012) to AR. The funder (SERB) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.