Frontiers in Immunology (Jun 2022)

Immunolipidomics Reveals a Globoside Network During the Resolution of Pro-Inflammatory Response in Human Macrophages

  • Sneha Muralidharan,
  • Sneha Muralidharan,
  • Federico Torta,
  • Federico Torta,
  • Michelle K. Lin,
  • Antoni Olona,
  • Marta Bagnati,
  • Aida Moreno-Moral,
  • Jeong-Hun Ko,
  • Shanshan Ji,
  • Bo Burla,
  • Markus R. Wenk,
  • Markus R. Wenk,
  • Hosana G. Rodrigues,
  • Enrico Petretto,
  • Enrico Petretto,
  • Enrico Petretto,
  • Jacques Behmoaras,
  • Jacques Behmoaras

DOI
https://doi.org/10.3389/fimmu.2022.926220
Journal volume & issue
Vol. 13

Abstract

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Toll-like receptor 4 (TLR4)-mediated changes in macrophages reshape intracellular lipid pools to coordinate an effective innate immune response. Although this has been previously well-studied in different model systems, it remains incompletely understood in primary human macrophages. Here we report time-dependent lipidomic and transcriptomic responses to lipopolysaccharide (LPS) in primary human macrophages from healthy donors. We grouped the variation of ~200 individual lipid species measured by LC-MS/MS into eight temporal clusters. Among all other lipids, glycosphingolipids (glycoSP) and cholesteryl esters (CE) showed a sharp increase during the resolution phase (between 8h or 16h post LPS). GlycoSP, belonging to the globoside family (Gb3 and Gb4), showed the greatest inter-individual variability among all lipids quantified. Integrative network analysis between GlycoSP/CE levels and genome-wide transcripts, identified Gb4 d18:1/16:0 and CE 20:4 association with subnetworks enriched for T cell receptor signaling (PDCD1, CD86, PTPRC, CD247, IFNG) and DC-SIGN signaling (RAF1, CD209), respectively. Our findings reveal Gb3 and Gb4 globosides as sphingolipids associated with the resolution phase of inflammatory response in human macrophages.

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