Anti-inflammatory Effects of Extracellular Cyclosporins Are Exclusively Mediated by CD147

Abstract

Leukocyte trafficking and recruitment is a critical process in host immune surveillance and in inflammatory diseases. Extracellular cyclophilins (eCyps) have been identified as a novel class of chemotactic mediators. The impact of eCyp/CD147 interactions for the recruitment of leukocytes during inflammation was analyzed using a structurally simplified cell-impermeable eCyp inhibitor. This compound was highly effective at inhibiting leukocyte migration toward CypA in vitro as well as in the recruitment of leukocytes during inflammation in a mouse model of experimentally induced peritonitis and delayed-type hypersensitivity reaction. By using CD147-/- mice in combination with the cell-impermeable eCyp inhibitor, we were able to show that the action of eCyps in inflammation is exclusively mediated by interaction with CD147. Our findings suggest that blocking eCyps may be an effective therapeutic target for reducing inflammatory diseases associated with leukocyte recruitment.

Insights into peptidyl-prolyl cis–trans isomerase structure and function in immunocytes

“…Knock-out of CD147 resulted in marked reduction of allergic contact hypersensitivity in mice, mainly because of decreased extravasation of myeloid cells and CD3+ T cells [97]. Furthermore, Malesevic and colleagues showed that in combination with the cell-impermeable derivative of CsA in CD147 −/− mice, the action of extracellular CyPs in inflammation is exclusively mediated by interaction with CD147 [97]. On the contrary, knocking out CyPA from mice (Ppia −/− ) increased tissue infiltration of immunocytes [82].…”

“…CD147 (also known as extracellular matrix metalloproteinase inducer or EMMPRIN) is a type I transmembrane protein belonging to the immunoglobulin superfamily and is the main signaling receptor for extracellular CyPs. Knock-out of CD147 resulted in marked reduction of allergic contact hypersensitivity in mice, mainly because of decreased extravasation of myeloid cells and CD3+ T cells [97]. Furthermore, Malesevic and colleagues showed that in combination with the cell-impermeable derivative of CsA in CD147 −/− mice, the action of extracellular CyPs in inflammation is exclusively mediated by interaction with CD147 [97].…”

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

“…MM284, a side-chain modification in the 1-position of cyclosporine A (CsA) was prepared according to published procedures (20). For injection, the powder was first dissolved in 100% ethanol (Sigma-Aldrich) and then diluted in sterile 15% solution of Cremophor EL (Sigma-Aldrich) in PBS.…”

Inhibition of Extracellular Cyclophilins with Cyclosporine Analog and Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

“…In this study we tested a cell-impermeable analog of CsA, MM284. MM284 is a CsA derivative that includes a negatively charged moiety coupled to presynthesized CsA (Malesevic et al, 2013;Seizer et al, 2015). The presence of this charged moiety prohibits passage of the compound through the plasma membrane, making it cell impermeable and capable of interacting with and inhibiting only extracellular pools of cyclophilins (Damsker et al, 2009).…”

“…-CsA), a cell-impermeable cyclosporine derivative that only binds to extracellular cyclophilins (Malesevic et al, 2013;Seizer et al, 2015), and compared the effect of MM284 to the effect of NIM811 ([Melle] 4 -CsA), a cellpermeable nonimmunosuppressive cyclosporine A derivative, on development of atherosclerosis in an animal model of atherosclerosis. Surprisingly, while MM284 did exert antiinflammatory activity, it exacerbated atherosclerosis.…”