From leukocyte recruitment to resolution of inflammation: the cardinal role of integrins

Abstract

Integrins constitute a large group of adhesion receptors that are formed as heterodimers of α and β subunits. Their presence and activation status on the surface of leukocytes modulate a broad spectrum of processes in inflammation and immunity. This mini review critically outlines research advances with regard to the function of leukocyte integrins in regulating and integrating the onset and resolution of acute inflammation. Specifically, we summarize and discuss relevant, current literature that supports the multifunctional role of integrins and their partners. The latter include molecules that physically associate with integrins or regulate their activity in the context of the following: 1) leukocyte recruitment to an inflamed tissue, 2) recognition and phagocytosis of apoptotic neutrophils (efferocytosis), and 3) egress of efferocytic macrophages from the inflamed site to lymphoid tissues. The understanding of the fine-tuning mechanisms of the aforementioned processes by integrins and their functional partners may enable the design of therapeutic tools to counteract destructive inflammation and promote more efficient resolution of inflammation.

Keywords: Del-1; adhesion; efferocytosis; neutrophils.

Figure 1.. The contribution of integrins to the shaping of several steps of acute inflammatory responses, including leukocyte recruitment or phagocytosis of apoptotic neutrophils.

Figure 2.. Integrin-dependent mechanisms drive the onset and resolution of acute inflammation.

Interaction between selectins and their glycosylated ligands promotes leukocyte rolling to endothelium. As a next step, leukocyte adhesion is mediated by the interaction among αMβ2, αLβ2, and α4β1 integrins with their counter-receptors (ICAMs, VCAM-1). The binding of β2 integrins to ICAMs or JAMs regulates transmigration that occurs mainly paracellularly. Integrins αvβ3/5 play a major role in the clearance of apoptotic neutrophils by phagocytes (efferocytosis). TSP-1, CCN1, and MFG-E8 act as bridging molecules that regulate recognition of PS that is exposed on apoptotic cells. Negative regulators of αvβ3-dependent efferocytosis include HMGB1, Vitronectin, and uPA. The β2 integrins αMβ2 and αXβ2 promote efferocytosis of apoptotic cells coated with the complement activation product iC3b. In the course of inflammation resolution, β2 integrins are also involved in macrophage egress to draining lymph nodes.