Pattern recognition receptors (PRR) expression and function in endothelial cells

By Victoria Osinski

What are Pattern recognition receptors?

Pattern recognition receptors (PRRs) recognize and respond to Pattern- and Damage-associated molecular patterns (PAMP and DAMPs) in a number of different cell types. The PRR family can be broken down into sub-families of receptors (Table 1). While first identified in the context of infection, these receptors and signaling pathways are involved in many disease contexts including ischemia, cancer, atherosclerosis, and autoimmunity.^2,16,18 Broadly, PRR signaling can regulate cell death¹, proliferation, cell activation, and pro-inflammatory cytokine expression via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and interferon regulatory transcription factor (IRF) transcriptional regulation.¹⁶ While PRRs are typically thought of as receptors expressed on immune cells, they are also expressed on non-immune cells where they play important functional roles.

Table 1. Pattern recognition receptors^{1,2,7,10,11,14}

Innate immunity signaling in the vasculature

Multiple studies have shown that PRRs are expressed on endothelial cells⁸, which are cells that line the innermost layer of all blood vessels. Endothelial cells are important in the translocation of immune cells from the circulation to sites of infection or injury and are essential for vascular function and homeostasis. PRR signaling in endothelial cells influences multiple functions including their activation and endothelial cell barrier function.^3-6,9,15 Many different PAMPs and DAMPs have been shown to bind to PRRs on endothelial cells including High mobility group box 1 (HMGB1), oxidized lipids, lipopolysaccharide (LPS), and Heat shock proteins (HSPs)^3-6,9,15,16.

Examples of PRR activity in endothelial cells:

• Activation of TLR2 and TLR6 on endothelial cells leads to production of pro-inflammatory and pro-angiogenic molecules IL-8 and TNF-alpha via MyD88 and NFκB. Generally, TLR2 and TLR6 promote angiogenesis.
• TLR4 signaling upregulates E-selectin, PECAM-1, MCP-1, and IL-6 expression in endothelial cells^3,5.
• Binding of DAMPs such as HMGB1 to RAGE in endothelial cells promotes maintenance of a tight endothelial barrier in blood vessels, which can be inhibited by increased presence of soluble RAGE. This mechanism is mediated by downstream beta-catenin and VE-cadherin signaling⁹.

Beyond endothelial cells, there are many other non-immune cell types such as vascular smooth muscle cells and adipocytes whose functions are affected by PRR signaling. Innate immune signaling in the vasculature is an emerging and exciting field relevant to many different disease settings including cancer, infection, and cardiovascular disease.