#BRIGHTWELL ALPHA ZIP SERIES#

Two of these, SIRPО± (also known as PTPNS1, SHPS1, CD172A and P84) and SIRPОі (also known as CD172b), are known to bind CD47. The SIRP family of proteins consists of five members SIRPО±, SIRPГџ1, SIRPГџ2, SIRPОі and SIRPОґ. In contrast to the more restricted expression pattern of SIRPО± (see below), CD47 is broadly expressed across different cell types in the body, with varying expression of the CD47 protein isoforms in different tissues ( Reinhold et al., 1995). In addition to binding SIRPО± and its family member SIRPОі, CD47 also interacts with integrins and secreted glycoprotein extracellular matrix protein thrombospondin-1 (TSP-1) (reviewed in ( Brown and Frazier, 2001) and ( Oldenborg, 2013)). The CD47 protein (also known as IAP, MER6 or OA3) consists of a single extracellular V-set IgSF domain, a presenilin domain with five membrane-spanning sections and a short cytoplasmic domain that is subject to alternative splicing, thereby giving rise to four isoforms ( Campbell et al., 1992 Mushegian, 2002 Reinhold et al., 1995). In this Perspective, we discuss the structural and functional properties of the CD47-SIRPО± axis and highlight the deficits in our understanding of the, possibly context-dependent, mechanisms that regulate CD47-SIPRО± signaling strength and that can be expected to influence the activity and toxicity of therapeutic targeting. In addition, a number of preclinical studies have provided compelling evidence for the potential value of the targeting of this axis in stem cell transplantation, and possibly also diseases such as atherosclerosis and fibrosis ( Kojima et al., 2016 Wernig et al., 2017)

#BRIGHTWELL ALPHA ZIP SERIES#

Next to an important role in these homeostatic processes, CD47 expression on cancer cells has been shown to inhibit myeloid cell-mediated elimination in a manner that bears a superficial resemblance to the inhibition of intratumoral T cell activity by the PD-1/PD-L1 immune cell checkpoint ( Sun et al., 2018).Д«ased on its role as a regulator of tumor cell fate, a series of molecules that block the CD47-SIRPО± axis is currently in clinical development in oncological indications, with an encouraging clinical signal in some settings. In particular, signaling through the CD47-SIRPО± axis has been shown to influence erythrocyte, platelet and hematopoietic stem cell (HSC) maintenance, and to regulate synaptic pruning during neuronal development ( Jaiswal et al., 2009 Lehrman et al., 2018 Lutz and Bogdanova, 2013 Yamao et al., 2002). Work over the past decades has demonstrated that the CD47-SIRPО± interaction regulates the outcome of myeloid cell-target cell crosstalk in a number of homeostatic processes. The latter class of inhibitory receptors, also known as immune checkpoints, includes a series of immunoreceptor tyrosine-based inhibitory (ITIM)- and immunoreceptor tyrosine-based switch motif (ITSM)-containing receptors such as SIRPО±, Leukocyte Immunoglobulin-like Receptor B1 (LILRB1), Siglec-10 and Programmed-cell Death Protein 1 (PD-1), which can bind CD47, MHC class I, CD24 and Programmed Death Ligand-1 (PD-L1) on target cells, respectively ( Barkal et al., 2019 2017 Gordon et al., 2017 Oldenborg et al., 2000). Target cell clearance or modification mediated by myeloid effector cells, including macrophages, neutrophils and microglia, is regulated by receptors that either transmit activating or inhibitory signals upon ligand binding.

In addition, the immune system plays a central role in tissue homeostasis by removing unnecessary cells or, in some cases, by modifying their interactions with surrounding cells. The immune system has evolved to detect and destroy target cells that are diseased, such as pathogen-infected or cancer cells that would potentially be harmful when not inactivated.

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