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sTREM2 Differentially Affects Cytokine Expression in Myeloid-Derived Cell Models via MAPK-JNK Signaling Pathway

Ryan Arsenault1,2, Steven Marshall2, Patrick Salois1

  • 1Human Health Therapeutics Research Centre, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada.

Biology
|February 23, 2024
PubMed

Insights

Soluble TREM2 (sTREM2) influences innate immune responses by modulating inflammatory cytokine expression in myeloid cells. This study reveals sTREM2 activates MAPK-JNK signaling and the NLRP3 inflammasome pathway.

Area of Science:

  • Immunology
  • Neuroscience
  • Cell Biology

Background:

  • Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is a key innate immune receptor on microglia and macrophages.
  • Mutations in TREM2 are associated with neurodegenerative diseases like Alzheimer's disease (AD).
  • Soluble TREM2 (sTREM2), cleaved from the cell membrane, shows altered levels during AD progression, but its role in innate immunity is unclear.

Purpose of the Study:

  • To investigate the inflammatory effects of sTREM2 on myeloid-derived THP-1 monocytes and macrophages.
  • To characterize the signaling mechanisms underlying sTREM2-induced inflammatory responses.
  • To explore the differential impact of sTREM2 on various macrophage subtypes (M0, M1, M2).

Main Methods:

  • Treatment of THP-1 cells and differentiated macrophages with sTREM2.
  • Analysis of inflammatory and anti-inflammatory cytokine expression over time.
  • Investigation of signaling pathways, including MAPK-JNK and NLRP3 inflammasome.
  • Use of TREM2 antibodies and NLRP3 inhibitors to probe molecular mechanisms.

Main Results:

  • sTREM2 stimulated inflammatory cytokine expression in THP-1 cells at early time points (2-8h) and anti-inflammatory cytokines later.
  • sTREM2 exhibited differential effects on M0, M1, and M2 macrophages, stimulating M0, having less effect on M2, and inhibiting M1 macrophages.
  • sTREM2-induced cytokine expression was primarily mediated by the MAPK-JNK pathway.
  • The sTREM2/TREM2 antibody complex activated the NLRP3 inflammasome pathway, increasing IL-1β expression.

Conclusions:

  • sTREM2 differentially modulates cytokine expression in various myeloid cell types.
  • The MAPK-JNK signaling pathway is a key mediator of sTREM2-induced cytokine responses.
  • sTREM2 and its antibody complex can activate the NLRP3 inflammasome, suggesting a role in inflammatory processes relevant to neurodegeneration.
Keywords:
MAPK–JNK signalingNLRP3 inflammasomeTHP-1 cellsTREM2cytokine expressioninflammatory responseinnate immune responsemacrophagemonocytessoluble TREM2 (sTREM2)

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