CD47 and thrombospondin-1 regulation of mitochondria, metabolism, and diabetes

Abstract

Thrombospondin-1 (TSP1) is the prototypical member of a family of secreted proteins that modulate cell behavior by engaging with molecules in the extracellular matrix and with receptors on the cell surface. CD47 is widely displayed on many, if not all, cell types and is a high-affinity TSP1 receptor. CD47 is a marker of self that limits innate immune cell activities, a feature recently exploited to enhance cancer immunotherapy. Another major role for CD47 in health and disease is to mediate TSP1 signaling. TSP1 acting through CD47 contributes to mitochondrial, metabolic, and endocrine dysfunction. Studies in animal models found that elevated TSP1 expression, acting in part through CD47, causes mitochondrial and metabolic dysfunction. Clinical studies established that abnormal TSP1 expression positively correlates with obesity, fatty liver disease, and diabetes. The unabated increase in these conditions worldwide and the availability of CD47 targeting drugs justify a closer look into how TSP1 and CD47 disrupt metabolic balance and the potential for therapeutic intervention.

Keywords: diabetes; fatty liver disease; metabolism; mitochondria; obesity.

Figure 1.

Direct and indirect effects of thrombospondin-1 (TSP1) on CD47 signaling. TSP1 is secreted under stress conditions and binds with high affinity to CD47, which is expressed on all cells. TSP1 binding induces CD47 signaling that alters cell metabolism, gene expression, and responses to stress. CD47 also interacts with signal regulatory protein-α (SIRPα) on different cells (trans interaction) and induces SIRPα signaling by altering the activity of phosphatases SHP1 and SHP2. Functional cis interactions between CD47 and SIRPα on the surface of a single cell have been reported but require further verification. TSP1 can also prevent cis and trans SIRPα signaling by inhibiting its binding to CD47. Conversely, therapeutic agents that target CD47 or SIRPα may also alter TSP1 interactions with CD47 to alter metabolism of glucose, fatty acids, and reactive oxygen species (ROS).

Figure 2.

Thrombospondin-1 (TSP1) impinges adversely on metabolic pathways and endocrine systems. TSP1 is upregulated by hypoxia, inflammation, hyperglycemia, high-fat intake, and age. Through activation of CD47 signaling, TSP1 adversely potentiates metabolic disease and diabetes via effects on mitochondrial homeostasis, metabolism, and survival in adipocytes and pancreatic islets. TSP1 signaling mediated by CD47 on vascular cells modulates angiogenesis and blood flow, and on macrophages and T cells modulates innate and adaptive immunity. CD47 interacting with signal regulatory protein-α (SIRPα) or SIRPγ further regulates innate and T cell immunity to impact metabolic disease.

Figure 3.

Thrombospondin-1 (TSP1) and CD47 in the pancreas. In isolated human islets, TSP1 is increased by elevated glucose, and CD47 is expressed in human pancreata. However, cell-specific expression analysis of both genes and their protein products is wanting. This is important, since islets are organoids with a unique vasculature and neural input, multiple endocrine cell types, and resident inflammatory cells. The signaling effects of altered TSP1 expression will depend on the source (endogenous vs. blood stream) and cell type. Given its immune modulatory actions, manipulation of TSP1 signaling with clinical antibodies targeting CD47 may unbalance innate immunity with possible adverse effects in pancreatic islets.