SIRP/CD47 signaling in neurological disorders

Highlights

• SIRP and CD47 regulate microglial activation.

• SIRP and CD47 mediate the interplay between microglia and other CNS cells.

• CD47 and SIRPα are important in neuroinflammation in the CNS disorders.

• CD47 and SIRPα may play janus roles in certain pathological events.

• Modulating CD47/SIRPα may have different effects depending on disease progress.

Abstract

Microglia play important roles in the process of neuronal injury and recovery. Numeous surface receptors have been described to regulate microglial activation. These receptors tightly mediate normal microglial functions including cell mobility, phagocytosis, and production of inflammatory mediators or trophic factors. In recent years, significant progresses have been achieved for understanding the signaling mechanisms underlying these receptors. Their specific roles in neurological diseases have been documented. This review will focus on the signal regulatory protein (SIRP) and its ligand CD47, two surface receptors expressed on microglia and other cells in the central nervous system (CNS) such as neurons. We will discuss the involvement of SIRP/CD47 signaling in microglial activation and in the interplay between microglia and other CNS cells. Current studies reveal the importance of CD47 and SIRPα in the process of neuroinflammation in the CNS disorders. The dual and contradictory role of CD47 suggests that targeting the SIRPα/CD47 signaling may achieve different effects depending on disease stage.

This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.

Introduction

About 20 years ago, microglia were first regarded as a distinct cell population in the central nervous system (CNS) with almost the same functions as peripheral macrophages (Barron, 1995). Nowadays, accumulating studies have highlighted the importance of microglia in CNS health and in the short and long-term progress of CNS diseases. On the one hand, microglial activation benefits the injured tissue by cleaning cell debris and reconstructing tissue integrity (Hanisch and Kettenmann, 2007, Lalancette-Hebert et al., 2007, Thored et al., 2009). On the other hand, excessive microglial activation may lead to secondary damage and impair CNS repair by releasing a bunch of harmful substances, including nitric oxide (NO), reactive oxygen species (ROS), and proinflammatory cytokines (Hu et al., 2015). Due to their janus-like roles, microglia are well-regulated by a variety of mechanisms so that they can be promptly switched on as the first responders to noxious stimuli and rapidly turned off to avoid unwanted effects. Many surface recognition receptors on microglia have been identified to sense the “turning on” or “turning off” signals released from other CNS cells and play critical role in modulating microglial responses in many CNS injuries and neurodegerative diseases (Hu et al., 2014).

The signal regulatory protein (SIRP, also known as CD172) and its ligand CD47 (also known as integrin-associated protein), are both expressed on the surface of microglia as well as on other types of CNS cells. Accumulating evidence documents that the interaction between SIRP and CD47 is important in mediating the cell–cell communication in the CNS. In this manuscript, we will discuss the functions of SIRP and CD47 in microglial activity and in the interplay between microglia and other CNS cells. The current understanding of the SIRP and CD47 sinaling will also be reviewed.

The SIRP is a family of surface receptors. The SIRP family consists of SIRPα, SIRPβ, and SIRPγ as well as some other closely related proteins. Among them, SIRPα and SIRPβ1 are mainly expressed on myeloid cells and have been detected on microglia (Gaikwad et al., 2009, Gitik et al., 2011). Interestingly, SIRPα and SIRPβ1 may play opposite roles on regulating microglial activities.

SIRPα (also known as SHPS-1, p84 and BIT) is expressed on a variety of myeloid cells. The activation of SIRPα has been related to the inhibition of cell activities, including the blunting of cytokine production (Kong et al., 2007, Latour et al., 2001, Smith et al., 2003), reduced monocyte adhesion to the extracellular matrix (Liu et al., 2005), reduced phagocytosis (Ide et al., 2007, Janssen et al., 2008, Latour et al., 2001, Oldenborg et al., 2000), and arrest of maturation of dendritic cells (Latour et al., 2001). In addition to these negative regulatory functions, a few positive effects of SIRPα have also been reported. For instance, engagement of SIRPα on monocytes mediates the transmigration of these cells across the endothelial lining of the blood–brain barrier (BBB) (de Vries et al., 2002). Ligation of SIRPα has also been shown to induce NO production from macrophages (Alblas et al., 2005). The expression of SIRPα on microglia is evident with immunohistochemical staining (Gitik et al., 2011). SIRPα is known to inhibit microglial phagocytic activity because the engulfment of myelin is augmented when microglial SIRPα is blocked with antibodies or knocked down by SIRPα-shRNA (Gitik et al., 2011). This inhibitory property of SIRPα is thought to be critical for the maintainence of myelin integrity under normal conditions or following mild brain damage. However, the inhibitory property of SIRPα may be disadvantageous in massive brain injuries or degeneration when rapid clearance of damaged myelin is essential.

In contrast to the negative functions of SIRPα discussed above, the activation of SIRPβ1 usually leads to cell activation. SIRPβ1 has been shown to positively regulate macrophage phagocytosis (Hayashi et al., 2004) and neutrophil migration (Liu et al., 2005). The expression of SIRPβ1 on microglia was upregulated in APP transgenic mice and in Alzheimer׳s disease (AD) patients (Gaikwad et al., 2009). Activation of SIRPβ1 on microglia by cross-linking antibodies induces reorganization of cytoskeletal proteins and increased microglial phagocytosis of microsphere beads, neural debris, and fibrillary Aβ. In contrast, lentiviral knockdown of SIRPβ1 impairs microglial phagocytosis of neural cell debris and Aβ. These findings support the hypothesis that ligation of SIRPβ1 triggers microglial phagocytosis. Interestingly, SIRPβ1 activation suppresses LPS-induced gene transcription of tumor necrosis factor α (TNFα) and nitric oxide synthase-2 in microglia, suggesting that the impact of SIRPβ1 on microglia might not be a simple binary function such as activation or suppression, but rather a subtler directional regulation geared toward maximizing the beneficial effects of microglia.