Nck1 is a critical adaptor between proatherogenic blood flow, inflammation, and atherosclerosis

Abstract

Atherosclerosis is an inflammatory condition of the arteries that has profound incidence and increasing prevalence. Although endothelial cells detect changes in blood flow, how endothelial activation contributes to atherogenic inflammation is not well understood. In this issue of the JCI, Alfaidi et al. used mouse models to explore flow-induced endothelial activation. The authors revealed a role for Nck1 and a specific activator of the innate immune response, the downstream interleukin receptor-associated kinase-1 (IRAK-1) in NF-κB-mediated inflammation and atherosclerosis susceptibility. These results link disturbed blood flow to NF-κB-mediated inflammation, which promotes atherosclerosis, and provide Nck1 as a potential target for the treatment of atherosclerosis.

Figure 1. Flow-dependent regulation of Nck1 adaptor and IRAK-1.

(A) In endothelial cells (ECs) under steady laminar flow (s-flow), homeostatic mechanisms are activated: flow mechanosensors include ion channels (e.g., TRPV4, TRPC1, Piezo1/2), G protein–coupled receptors and heterotrimeric G proteins (Gαq/11), and the primary cilium; the junctional complex (containing Vegfr2/Flk-1, VE-cadherin, and PECAM-1) detects EC-EC junctions, and the basal mechanosensors (integrin receptors) linked to the extracellular matrix detect adhesion. Receptor tyrosine kinases (RTKs) present in ECs are EGFR, Fgfr-1, and Vegfr2; the SH2 domains of Nck1 and 2 may bind to RTKs. In s-flow, downstream of flow sensors and RTK, the kinases MEKK2/3 activate MEK5 and phosphorylate ERK5, which activates transcription factors KLF-2/KLF-4, leading to increases in eNOS and VEGFR2 to promote quiescence. (B) A simplified diagram of ECs under disturbed flow (d-flow) focuses on the Nck/IRAK-1 pathway to inflammation. An unknown mechanosensor signals to promote the binding of Nck1 to IRAK-1 under d-flow, which may involve Nck1 binding to PECAM-1 (5). Nck1 was shown previously to bind to the kinase PAK2 (6). The direct interaction with Nck1 leads to IRAK-1 phosphorylation, possibly by PAK2, to become active. p-IRAK-1 then phosphorylates IκB kinase (IKK), which in turn phosphorylates IκB and p65; IκB releases p65, which translocates to the nucleus to upregulate proinflammatory gene expression (e.g., VCAM1, ICAM1, IL-1, IL-6, and MCP-1).