Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

Abstract

Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1's immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition-the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery-the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation.

Keywords: PD-L1; PD-L2; atherosclerosis and blood vessel inflammatory diseases; coronary artery disease; programmed death-1 (PD-1).

Figure 1

Role of PD-L1 on vascular endothelial cell injury and barrier functions. Regulation of blood vessel inflammation by PD-L1/PD-1 axis. An increased shear stress causes vascular endothelial cells (VECs) to produce nitric oxide (NO) from L-arginine in the presences of one of the several nitric oxide synthase (eNOS) cofactors, such as tetrahydrobiopterin (BH4). The generation of NO leads to vasodilation of smooth muscle cells (SMCs) and increases the VECs’ permeability. The cofactor, BH4, prohibits the PD-L1 gene transcription and reduces the expression of PD-L1 proteins on VECs. (1) Minimally expressed PD-L1 molecules have a higher possibility of binding to PD-1 molecules in cis, expressed on VECs. Diminished expression of PD-L1 boost the aggressiveness of pro-atherogenic CD8⁺ T cells, leading to VEC injury via cytolytic enzymes such as perforin and pro-inflammatory cytokines, TNF-α and IFN-γ. This insult to the VECs results in the expression of pro-apoptotic genes and enhances VEC apoptosis. (2) The released IFN-γ from CD8⁺ T cells binds to IFN-γ receptors and further induces PD-L1 protein expression on VEC surfaces. Increased PD-L1 hampers zonula occludens-1 (ZO-1), which regulates the expression of tight junctional molecules. PD-L1-mediated ZO-1 dysregulation shatters the junctional proteins, which breaches the VEC barrier causing leakage. The enhanced PD-L1 molecules also increased the angiopoietin (ang-2), an inflammatory marker, that act via its receptor Tie 2 and are tightly controlled by foxO1 transcription factor. However, the potential link between foxO1 and PD-L1 remains obscure. The cell-adhesion molecules, ICAM-1 and VCAM, are upregulated by VECs under the influence of ang-2. In turn, VEC-released ang-2 recruits neutrophils to the site, where neutrophils are sensitized to produce myeloperoxidase (MPO) and results in severe inflammation.

Figure 2

Possible mechanistic link between PD-1 and PD-L1 molecules and an altered lipid metabolism on different types of cells during vascular inflammation. Possibly, (1) an increased uptake and intracellular accumulation of lipids in VECs might induce (i) oxidative stress to mitochondria as reflected by ROS production; (ii) cell surface expression of VCAM and ICAM-1 adhesion molecules; (ii) increased secretion of monocyte chemoattractant proteins (MCP-1); (iii) increased transcriptional factor NF-κB and activator protein-1 (AP-1) expression; (iv) increased TNF-α levels; (v) decreased VEC tight junctional protein regulator, (ZO-1); (vi) enhanced permeability and increased VEC apoptosis. The lipid uptake by VECs is indeed aided by the increased PD-L1 levels through the upregulation of fatty acid-binding proteins (Fabp4/5). (2) The circulating lipids are also uptaken by bystander PD-1highCD8⁺ T cells that promotes fatty acid oxidation via carnitine palmitoyl transferase (CPT1A), the rate-limiting enzyme of FAO, to sustain T cell survival and longevity. (3) Reduced CTRP13 in CAD macrophages prohibit the autophagy flux (AF) to clear the accumulated lipids that are taken via the scavenger receptor, CD36. This tends to load the CAD macrophage with circulating lipids to convert them into a foam cell, which is a key cell type with altered phenotype and metabolism in atherosclerotic plaques.