Thrombospondin-1: multiple paths to inflammation

Abstract

Inflammation is a defensive process against tissue injury. Once this self-protective strategy is initiated, an effective resolution of the process is crucial to avoid major and unnecessary tissue damage. If the underlying event inducing inflammation is not addressed and homeostasis is not restored, this process can become chronic and lead to angiogenesis and carcinogenesis. Thrombospondin-1 (TSP-1) is a matricellular protein involved in angiogenesis, cancer, and inflammation. The effects of TSP-1 have been studied in many preclinical tumor models, and mimetic peptides are being tested in cancer clinical trials. However, the molecular mechanisms explaining its role in inflammatory processes are not well understood. This paper will discuss the role of TSP-1 in inflammation and its interaction with key receptors that may explain its functions in that process. Recent literature will be reviewed showing novel mechanisms by which this multifaceted protein could modulate the inflammatory process and impact its resolution.

Figure 1

Schematic representation of the structure of TSP-1 and its receptor sites. TSP-1 is a large, homotrimeric molecule (420 kDa). Each monomer consists of an interchain disulfide bond (S=S), procollagen homology domain (PC), Type I, II, and III repeats. The amino and carboxyl terminals are globular [8]. RFK and RGDA are the binding sites for TGFβ and the integrins, respectively. CSVTCG is the receptor site for CD36. The C-terminal domain of TSP-1 binds CD47. TSP-1 mimetic peptides have been designed from the heptapeptide GVITRIR of the second type-1 repeat. ABT-526 and ABT-510 are nonapeptides and enantiomers of each other, where D-Ile was replaced with D-allo-Ile in ABT-510 [33]. Sar, Nva, and NHEt are abbreviations for sarcosine, norvaline, and ethylamide. A second generation mimetic peptide, ABT-898, has been reported to have increased potency and slower clearance [95]. These peptides have been used in clinical studies for their antiangiogenic properties. Recombinant fragment rTSP1_793–824 has been studied in experimental erosive arthritis [72].

Figure 2

Dual role of CD-36—TSP-1 interaction in inflammation. Expression of CD36 is positively regulated by PPARγ and negatively regulated by TGFβ. As an integral membrane protein, CD36 binds many ligands including TSP-1. The CD36-TSP-1 interaction involves conformational changes in TSP-1. This interaction mediates apoptotic effects via the CD47-dependent pathway, which has multiple effects. The CD36-TSP-1 interaction can also activate macrophage TGFβ1 and the NFκB pathway *[98, 99], **[–102], ^†[100], ^‡[103]. Blue shading indicates pathways occurring in endothelial cells, pink shading in macrophages, and yellow shading in epithelial cells.

Figure 3

The homotrimeric TSP-1 activates latent TGFβ1 by binding the N-terminal propeptide LAP and the mature TGFβ1. The binding results in conformational changes in TGFβ1 and allows TGFβ1 to be recognized by its receptor. Mature, active TGFβ1 has been reported to decrease dendritic cell maturation and activate T cells. An opposing role of TGFβ1 results in fibrosis.