Endothelial Dysfunction and Inflammation: Immunity in Rheumatoid Arthritis

Abstract

Inflammation, as a feature of rheumatoid arthritis (RA), leads to the activation of endothelial cells (ECs). Activated ECs induce atherosclerosis through an increased expression of leukocyte adhesion molecules. Endothelial dysfunction (ED) is recognized as a failure of endothelial repair mechanisms. It is also an early preclinical marker of atherosclerosis and is commonly found in RA patients. RA is now established as an independent cardiovascular risk factor, while mechanistic determinants of ED in RA are still poorly understood. An expanding body of study has shown that EC at a site of RA is both active participant and regulator of inflammatory process. Over the last decade, a role for endothelial dysfunction in RA associated with cardiovascular disease (CVD) has been hypothesized. At the same time, several maintenance drugs targeting this phenomenon have been tested, which has promising results. Assessment of endothelial function may be a useful tool to identify and monitor RA patients.

Figure 1

ECs and innate and adaptive immunity. Part A. Innate immunity: (1) ECs express CD36 scavenger receptor and the TLRs, which trigger signals resulting in proinflammatory gene expression, leukocyte chemotaxis, phagocytosis, cytotoxicity, and activation of adaptive immune responses. (2) Receptors NODs 1 and 2 work as sensors for microbial peptides and regulators of inflammation. (3) ECs respond to invading microbes and endogenous substances by producing inflammatory mediators and expressing surface molecules, such as CD40, CD80, CD86, CD134L, PD-L1, and PD-L2. Part B. Adaptive immunity: (4) Activated ECs express costimulators including OX40 ligand and 4-1BB ligand, which are involved in formation, activation, and survival of memory T cell. (5) ECs express MHC I and MHC II class molecules and process antigen. (6) ECs secrete cytokines, such like IL-1, -6, -8, -25, -33, TNF-α. TNFα, and TSLP, which regulate and shape adaptive and innate immune responses to control the recruitment and influx of immune cells to sites of action.

Figure 2

ECs are essential for angiogenesis in RA. VEGF secreted by ECs and other cells inducing angiogenesis by acting on ECs, promoting cell mitogenesis, cell migration, and lumen formation. TNF-α can enhance chemokine expression, ECs activation, and angiogenesis. In addition, TNF-α, IL-1, and IL-6 can cause bone damage. IL-6 can induce VEGF production in RA FLS and increase permeability and cell infiltration. IL-6, endocan, and IL-18 can also induce angiogenesis. Angiogenic chemokines activate ECs through chemokine receptor CXCR2, CXCR4, and CXCR7 and then induce angiogenesis.