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The chemotherapeutic drug carboplatin affects macrophage responses to LPS and LPS tolerance via epigenetic

Atsadang Boonmee1,2, Salisa Benjaskulluecha2,3, Patipark Kueanjinda2,4

  • 1Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.

Scientific Reports
|November 4, 2021
PubMed

Insights

Carboplatin, an anticancer drug, can reverse lipopolysaccharide (LPS)-induced immunosuppression in macrophages. This occurs by modulating epigenetic factors, potentially restoring proinflammatory cytokine production.

Area of Science:

  • Immunology
  • Epigenetics
  • Pharmacology

Background:

  • Macrophages develop an immunosuppressive state, termed LPS tolerance, upon re-exposure to lipopolysaccharide (LPS), characterized by reduced proinflammatory cytokine production.
  • LPS tolerance involves epigenetic modifications that regulate gene expression.
  • Carboplatin, a chemotherapy agent, impacts DNA replication, transcription, and epigenetic processes.

Purpose of the Study:

  • To investigate the effect of carboplatin on LPS-induced tolerance in macrophages.
  • To identify molecular mechanisms underlying carboplatin's impact on macrophage function.

Main Methods:

  • Unbiased screening to identify carboplatin's effect on cytokine production.
  • Transcriptomic analysis and gene set enrichment analysis (GSEA).
  • Analysis of Heterochromatin protein 1 (HP1-α) and H3K9me3-related gene expression at mRNA and protein levels.

Main Results:

  • Carboplatin treatment rescued TNF-α and IL-6 production in LPS-tolerant macrophages.
  • p53 was significantly upregulated, while E2F and G2/M cell cycle phases were downregulated in carboplatin-treated LPS-tolerant macrophages.
  • HP1-α expression decreased, and dynamic changes in H3K9me3 methyltransferases (setdb2, kdm4d, suv39h1) were observed.

Conclusions:

  • Carboplatin interferes with proinflammatory cytokine production in both acute LPS response and LPS tolerance.
  • The mechanism may involve carboplatin's influence on H3K9me3 epigenetic modifications.
  • Carboplatin demonstrates potential in modulating macrophage immune responses.

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