Differentiation of human macrophages with anaphylatoxin C3a impairs alternative M2 polarization and decreases lipopolysaccharide-induced cytokine secretion

Denis A. Mogilenko, Katerina Danko, Ekaterina E. Larionova, Vladimir S. Shavva, Igor V. Kudriavtsev, Ekaterina V. Nekrasova, Alexandra V. Burnusuz, Nikolay P. Gorbunov, Alexander V. Trofimov, Alexander V. Zhakhov, Igor A. Ivanov, Sergey V. Orlov

Research output: Contribution to journalArticlepeer-review

Abstract

Anaphylatoxin C3a is a small signaling polypeptide that is generated during complement activation. C3a is involved in the regulation of various innate and adaptive immune system processes; however, the role of C3a in macrophage differentiation and polarization is poorly elucidated. Here we showed that C3a impairs alternative M2 polarization of human macrophages and suppressed CD206, IL1Ra and CCL22 expression. C3a leads to a decrease of nuclear receptor PPARγ expression via the ERK1/2 signaling pathway, resulting in repressed PPARγ-dependent activation of CD36, FABP4 and LXRα genes and blunted response to an LXR ligand TO901317. Using small interfering RNA and agonist/antagonist approaches we showed that C3a decreases CD206, IL1Ra and CCL22 transcription at least partly in a PPARγ-dependent manner in M2 macrophages. Moreover, C3a impairs efferocytosis by M2 macrophages and inhibits their migratory activity. By contrast, macrophages treated with C3a during differentiation show blunted response to lipopolysaccharide stimulation owing to downregulation of TLR4 and lipid raft content. At the same time, differentiation of macrophages with C3a does not change M1 polarization in interferon gamma (IFNγ) and IFNγ + lipopolysaccharide–treated macrophages. These data provide a novel role of complement system and C3a in the regulation of M2 macrophage polarizations and suggest crosstalk between C3a, TLR4, PPARγ and LXR signaling pathways.

Original languageEnglish
Pages (from-to)186-204
Number of pages19
JournalImmunology and Cell Biology
Volume100
Issue number3
DOIs
StatePublished - Mar 2022

Keywords

  • Anaphylatoxin C3a
  • LXR
  • M1 macrophages
  • M2 macrophages
  • PPARγ
  • TLR4

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