Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics

Abstract

CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Among these CD147-interacting proteins cyclophilins represent a particularly interesting class, both in terms of structural considerations and potential medical implications. CD147 has been shown to function as a signalling receptor for extracellular cyclophilins A and B and to mediate chemotactic activity of cyclophilins towards a variety of immune cells. Recent studies using in vitro and in vivo models have demonstrated a role for cyclophilin-CD147 interactions in the regulation of inflammatory responses in a number of diseases, including acute lung inflammation, rheumatoid arthritis and cardiovascular disease. Agents targeting either CD147 or cyclophilin activity showed significant anti-inflammatory effects in experimental models, suggesting CD147-cyclophilin interactions may be a good target for new anti-inflammatory therapeutics. Here, we review the recent literature on different aspects of cyclophilin-CD147 interactions and their role in inflammatory diseases.

Fig. 1

Schematic representation of CD147 and its interactions. (a) Matrix metalloproteinase (MMP) induction is mediated by a homotypic interaction between CD147 molecules on different cells; chemotactic responses are initiated by interaction between cyclophilin and CD147. Immunoglobulin 1 (Ig1) domain is involved in MMP induction, whereas proline 211 and possibly proline 180 are required for interaction with cyclophilins and for cyclophilin-induced signalling. Glutamic acid in position 218 is potentially involved in interactions with other transmembrane proteins, such as CD43, β1 integrin and syndecan. The relevance of these interactions to disease pathogenesis is described in the text. (b) Potential model of CD147 homophilic interactions. A recently solved structure of CD147 Ig1 domain alone has revealed that the C-terminal beta-strand of one subunit is swapped with that of the other subunit [99]. It is still unclear how this process is regulated. See text for details.