Contribution of vascular cell-derived cytokines to innate and inflammatory pathways in atherogenesis

Introduction Atherosclerosis - overview General remarks Early atherosclerosis Exogenous and/or infectious activators Endogenous activators Later phases of atherosclerosis Innate and inflammatory pathways in atherogenesis Innate receptors PAMP and DAMP Pentraxins NOD-like proteins/receptors (NLRs) toll-like receptors (TLRs) Knockout of pattern recognition molecules reduces atherosclerosis Innate cytokines The innate cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) TNF-/- ApoE-/- mice are less atherosclerotic IL-1-/- ApoE-/- mice are less atherosclerotic Monocyte chemoattractant protein-1 and fractalkine IL-6 activates innate pathways and is produced by cardiovascular cells Functions of IL-6 important for atherogenesis Role of trans-signalling in cardiovascular inflammation Animal experiments suggest a role for the IL-6 system in atherosclerosis Cytokine-mediated interaction of vessel wall cells and leucocytes Endothelial cell (EC)-monocyte interaction Smooth muscle cell (SMC)-EC interaction SMC-monocyte and SMC-T cell interaction Summary and conclusion Future perspectives Which initiator(s) starts atherogenesis? Is there more than one starting point? What are the specific roles of the various cytokines in the vessel wall? Are treatments addressing different phases of atherogenesis of advantage? What about prevention? What are the expectations? Inflammation is a central element of atherogenesis. Innate pathways contribute to vascular inflammation. However, the initial molecular process(es) starting atherogenesis remain elusive. The various risk factors, represented by particular compounds (activators), may cause altered cellular functions in the endothelium (e.g. vascular endothelial cell activation or -dysfunction), in invading cells (e.g. inflammatory mediator production) or in local vessel wall cells (e.g. inflammatory mediators, migration), thereby triggering the innate inflammatory process. The cellular components of innate immunology include granulocytes, natural killer cells and monocytes. Among the molecular innate constituents are innate molecules, such as the toll-like receptors or innate cytokines. Interleukin-1 (IL-1) and IL-6 are among the innate cytokines. Cytokines are potent activators of a great number of cellular functions relevant to maintain or commove homeostasis of the vessel wall. Within the vessel wall, vascular smooth muscle cells (SMCs) can significantly contribute to the cytokine-dependent inflammatory network by: (i) production of cytokines, (ii) response to cytokines and (iii) cytokine-mediated interaction with invading leucocytes. The cytokines IL-1 and IL-6 are involved in SMC-leucocyte interaction. The IL-6 effects are proposed to be mediated by trans-signalling. Dysregulated cellular functions resulting from dysregulated cytokine production may be the cause of cell accumulation, subsequent low-density lipoprotein accumulation and deposition of extracellular matrix (ECM). The deposition of ECM, increased accumulation of leucocytes and altered levels of inflammatory mediators may constitute an 'innate-immunovascular-memory' resulting in an ever-growing response to anew invasion. Thus, SMC-fostered inflammation, promoted by invading innate cells, may be a potent component for development and acceleration of atherosclerosis.