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.
Highlights
Microglial cells, the only population of myeloid origin in the brain parenchyma, constitute the first line of defense of the central nervous system (CNS) [1]
In this report we have shown that cultured microglia express mRNA encoding for all the members of the CMRF-35–like molecules (CLM) family, supporting the idea that these molecules could modulate the function of microglial cells
Focusing in CMRF35-like molecule-1 (CLM-1), we have demonstrated that this receptor is present on the surface of cultured microglia, and that its expression is modulated differently by diverse pro-inflammatory stimuli
Summary
Microglial cells, the only population of myeloid origin in the brain parenchyma, constitute the first line of defense of the central nervous system (CNS) [1]. Microglia undergo a profound change of their functional phenotype from the resting/ surveying state to an heterogeneous activation state, which has been defined as effector state [3]. This effector state is characterized by an increase of the proliferation, migration, phagocytosis and the production of a broad range of both pro-inflammatory and anti-inflammatory mediators [4]. Several members of the immunoglobulin superfamily such as CD200R, TREM-2 or SIGLECs have been reported to be key regulators of microglial activation, and its dysfunction has been implicated in different CNS pathologies such as Multiple Sclerosis or Alzheimer’s Disease [8,9,10]
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