ABSTRACT
Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications, myocardial infarction and stroke, are the leading cause of mortality worldwide [1], [2]. Recent studies have identified Triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions [3], to be highly expressed in macrophage foam cells in experimental and human atherosclerosis [4]. However, the role of TREM2 in atherosclerosis is not fully known. Here, we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages, and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis.
ABSTRACT
Micro-RNAs (miRNAs) are highly evolutionarily conserved short-length/noncoding RNA molecules that modulate a wide range of cellular functions in many cell types by regulating the expression of a variety of targeted genes. miRNAs have also recently emerged as key regulators of neuronal genes mediating the effects of psychostimulant drugs and memory-related neuroplasticity processes. Smoking is a predominant addictive behaviour associated with millions of deaths worldwide, and nicotine is a potent natural psychoactive agonist of cholinergic receptors, highly abundant in cigarettes. The influence of miRNAs modulation on cholinergic signalling in the nervous system remains however poorly explored. Using miRNA knockout mice and biochemical, electrophysiological and pharmacological approaches, we examined the effects of miR-132/212 gene disruption on the levels of hippocampal nicotinic acetylcholine receptors, total ERK and phosphorylated ERK (pERK) and MeCP2 protein levels, and studied the impact of nicotine stimulation on hippocampal synaptic transmission and synaptic depression and strengthening. miR-132/212 deletion significantly altered α7-nAChR and pERK protein levels, but not total ERK or MeCP2, and resulted in both exacerbated synaptic depression and virtually abolished memory-related synaptic strengthening upon nicotine stimulation. These observations reveal a functional miRNAs/nicotinergic signalling interplay critical for nicotinic-receptor expression and neuroplasticity in brain structures relevant for drug addiction and learning and memory functions.
