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Atherosclerosis: cell biology and lipoproteins-focus on CD40 signaling, PCSK9, and novel animal models.

DOI:10.1097/MOL.0000000000000185 Atherosclerosis is a chronic inflammatory disease of the arterial wall. Injurious stimuli including shear stress and modification of lipoproteins and its subendothelial deposition activate the endothelium [1]. Inflammatory cells of the innate and the adaptive immune system are recruited to the subendothelial space promoting atherosclerotic plaque development through immunological interactions. CD40– CD40L interaction is a central pathway regulating the immune response in several inflammatory conditions including atherosclerosis [2,3]. Inhibition of CD40 ligand (CD40L, CD154) in apolipoprotein Edeficient (Apoe / ) mice not only reduced atherosclerosis but also conferred a clinically favorable plaque phenotype that was low in inflammation and high in fibrosis [4,5]. Interestingly, we and others recently found that genetic ablation or pharmacologic inhibition of CD40L also ameliorated adipose tissue inflammation and insulin resistance in a mouse model of diet-induced obesity [6,7]. In particular, CD40L deficiency led to lower CD8þ T cell content and increased numbers of anti-inflammatory regulatory T cells in obese visceral adipose tissue [7]. Although bearing potential as a therapeutic target, blockade of CD40L may not be therapeutically feasible, as long-term inhibition will compromise systemic immune responses and may lead to thrombotic complications [8]. Accordingly, we have recently developed small molecules to interrupt the interaction of CD40 with one of its downstream signaling partners [tumour necrosis factor receptorassociated factor (TRAF)-6] leading to amelioration of complications evoked by obesity [9,10]. Interestingly, Wolf et al. [11] showed that CD40 signaling led to less adipose tissue inflammation whereas T cellspecific inhibition exacerbated disease complication. These contrasting outcomes highlight the need for more cell-specific therapeutic strategies and improved experimental models. In addition classical conditional-targeting methods, novel genome engineering technologies provide promising opportunities to study