Inflammation and vascular injury: basic discovery to drug development

Abstract

The invited special lecture at the 76(th) Annual Scientific Meeting of the Japanese Circulation Society focused on the central role of inflammation in vascular injury and repair. Early studies pioneered the concept that mechanical injury, such as balloon angioplasty and endovascular stent deployment, elicits an inflammatory response from the vessel wall. This hypothesis was developed and substantiated at a time when the prevailing dogma viewed restenosis following angioplasty as a primarily proliferative smooth muscle cell disease. Antibody targeting of Mac-1 reduced leukocyte accumulation and limited neointimal formation following balloon injury or stent implantation. Genetic absence of Mac-1 resulted in diminished leukocyte accumulation and neointimal thickening after carotid artery injury in mice. In the course of those studies, our laboratory made fundamental discoveries regarding the mechanism of leukocyte recruitment at sites of vascular injury and identified platelet glycoprotein (GP) Ibα, a component of the GPIb-IX-V complex, as the previously unknown platelet counter-receptor for Mac-1. Follow-on studies have focused extensively on the structure, function, and signaling of the leukocyte integrin Mac-1. The binding site for GPIbα in Mac-1 has been mapped and subsequently showed that leukocyte engagement of platelet GPIbα via Mac-1 is critical not only for the biological response to vascular injury, but also for thrombosis, vasculitis, glomerulonephritis, and multiple sclerosis, thereby advancing the hypothesis that virtually all inflammation is platelet-dependent. Furthermore, ligand engagement of Mac-1 initiates a novel gene program that promotes inflammation by activating NFκB and downregulating the expression of the forkhead transcription factor Foxp1 that controls monocyte differentiation. Small molecule inhibitors of Mac-1 function have been pursued, including targeting of Mac-1-GPIbα binding or the downstream tyrosine kinase spleen tyrosine kinase. Drs Teruo Inoue, Koichi Node, Tatsuya Fukotomi, Masashi Sakuma, Toshifumi Morooka, and Kohsuke Nakajima, valued Japanese collaborators and post-doctoral fellows, have contributed enormously to these discoveries.

Figure 1

Leukocyte recruitment at site vascular injury with endothelial denudation and platelet deposition. Sequential adhesion cascade of leukocyte attachment to and transmigration across surface-adherent platelets involves the initial tethering and rolling of leukocytes on platelet P-selectin and is followed by firm leukocyte adhesion and transplatelet migration, processes that are dependent on leukocyte Mac-1 and platelet receptors, including GPIbα, JAM-3, and fibrinogen bound to GPIIb/IIIa.

Figure 2

Mac-1 signaling, monocyte differentiation and pro-inflammatory gene expression. Mac-1 engagement and clustering recruits a Toll/IL-1 receptor family-like cascade involving IRAK1 (IL-1 receptor-associated kinase), TRAF-6 (TNF- receptor-associated factor 6) and TAK-1 (TGF-β-activated kinase) to modulate NFκB activity. Clustering of Mac-1 also leads to downregulation of Foxp1, which functions as a transcriptional repressor of the MCSF-1 (macrophage colony-stimulating factor) receptor, c-fms. Leukocyte integrin signaling pathways converge on spleen tyrosine kinase (Syk), a 72-kDa signaling protein with kinase and scaffolding activities.