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Role of MMPs in orchestrating inflammatory response in human monocytes via a TREM-1-PI3K-NF-κB pathway

Vanesa Gómez-Piña1, Eriel Martínez, Irene Fernández-Ruíz

  • 1Laboratory of Tumor Immunology, IdiPAZ, La Paz Hospital, Madrid, Spain

Journal of Leukocyte Biology
|March 31, 2012
PubMed

Insights

Matrix metalloproteinases (MMPs) regulate TREM-1, a key immune modulator. Inhibiting MMPs sustains TREM-1, preventing monocyte inflammatory responses and suggesting an adaptive innate immunity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs) are enzymes involved in inflammatory processes.
  • TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) is a key modulator of innate immune responses.
  • MMPs shed the ectodomain of TREM-1, generating soluble TREM-1 (sTREM-1), which has anti-inflammatory properties, contrasting with membrane-bound TREM-1's pro-inflammatory role.

Purpose of the Study:

  • To investigate the role of sustained cell surface TREM-1 expression in human monocytes.
  • To elucidate the mechanisms by which TREM-1 and MMPs modulate monocyte responses to endotoxin.
  • To determine if sTREM-1 can induce alternative activation (ET) in naive monocytes.

Main Methods:

  • Inhibition of metalloproteinases to sustain TREM-1 on the surface of human monocytes.
  • Analysis of cytokine profiles and other features of the endotoxin tolerance (ET) phenotype.
  • Investigation of the involvement of PI3K and Syk signaling pathways.
  • Assessment of sTREM-1's effect on proinflammatory responses and ET induction.

Main Results:

  • Sustained cell surface TREM-1 expression counteracted the downregulation of proinflammatory cytokines during endotoxin tolerance (ET).
  • Stabilization of TREM-1 at the cell surface underdeveloped other features of the ET phenotype, mediated by PI3K and Syk.
  • sTREM-1 counteracted the proinflammatory response of stabilized membrane TREM-1 but did not induce ET in naive monocytes.
  • Sustained TREM-1 expression blocked the development of a refractory state in human monocytes.

Conclusions:

  • TREM-1 and MMPs orchestrate an adaptive form of innate immunity.
  • Modulation of human monocyte response to endotoxin is achieved through TREM-1 and MMPs.
  • Sustained TREM-1 surface expression is sufficient to prevent monocyte refractoriness.

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