The Receptor CMRF35-Like Molecule-1 (CLM-1) Enhances the Production of LPS-Induced Pro-Inflammatory Mediators during Microglial Activation

PLoS One. 2015 Apr 30;10(4):e0123928. doi: 10.1371/journal.pone.0123928. eCollection 2015.

Abstract

CMRF35-like molecule-1 (CLM-1) belongs to a receptor family mainly expressed in myeloid cells that include activating and inhibitory receptors. CLM-1 contains two ITIMs and a single immunoreceptor tyrosine-based switch motif (ITSM), although also displays a binding site for p85α regulatory subunit of PI3K. By using murine primary microglial cultures, we show the presence of all CLM members in microglial cells and characterize the expression of CLM-1 both in basal conditions and during microglial activation. The TLR4 agonist lipopolysaccharide (LPS) and the TLR3 agonist polyinosinic-polycytidylic acid (Poly I:C) induce an increase in microglial CLM-1 mRNA levels in vitro, whereas the TLR2/6 heterodimer agonist peptidoglycan (PGN) produces a marked decrease. In this study we also describe a new soluble isoform of CLM-1 that is detected at mRNA and protein levels in basal conditions in primary microglial cultures. Interestingly, CLM-1 engagement enhances the transcription of the pro-inflammatory mediators TNFα, COX-2 and NOS-2 in microglial cells challenged with LPS. These results reveal that CLM-1 can acts as a co-activating receptor and suggest that this receptor could play a key role in the regulation of microglial activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cyclooxygenase 2 / biosynthesis*
  • Gene Expression Regulation / drug effects
  • Inflammation Mediators / metabolism*
  • Lipopolysaccharides / toxicity*
  • Mice
  • Microglia / metabolism*
  • Microglia / pathology
  • NIH 3T3 Cells
  • Nitric Oxide Synthase Type II / biosynthesis*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Poly I-C / pharmacology
  • Receptors, Immunologic / biosynthesis*
  • Toll-Like Receptors / agonists
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis*

Substances

  • CLM-1 protein, mouse
  • Inflammation Mediators
  • Lipopolysaccharides
  • Receptors, Immunologic
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Poly I-C

Grants and funding

This work was supported by grants from Fondo de Investigaciones Sanitarias (PI1100045), Fundació “La Marato de Tv3” (110532 and 110533), Comisión Sectorial de Investigación Científica (CSIC-UDELAR), Agencia de Gestio d’Ajuts Universitaris i de Recerca de Catalunya (AGAUR) (2009 SGR 493), Agencia Nacional de Investigación e Innovación (ANII), PEDECIBA, and FOCEM (MERCOSUR Structural Convergence Fund), COF 03/1111. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.