Synergy between a plasminogen cascade and MMP-9 in autoimmune disease
Zhi Liu, … , Robert M. Senior, Zena Werb
Zhi Liu, … , Robert M. Senior, Zena Werb
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):879-887. https://doi.org/10.1172/JCI23977.
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Article Autoimmunity

Synergy between a plasminogen cascade and MMP-9 in autoimmune disease

Abstract

Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9–deficient mice to the skin disease. In addition, MMP-3–deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.

Authors

Zhi Liu, Ning Li, Luis A. Diaz, Michael Shipley, Robert M. Senior, Zena Werb

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Figure 5

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Blocking plasmin activity abolishes experimental BP. To demonstrate that...
Blocking plasmin activity abolishes experimental BP. To demonstrate that α2-AP treatment blocks plasmin activity and subsequent MMP-9 activation and blistering, WT mice were injected i.d. with pathogenic anti-mBP180 IgG (2.64 mg/g body weight) followed by local administration of PBS, the plasmin inhibitor α2-AP, or the neutrophil cathepsin G inhibitor α1-AC. Mice were examined at 12 hours after IgG injection. (A) Pathogenic anti-mBP180 IgG induced high levels of neutrophil infiltration and subepidermal blisters in +/+ mice (bar 1) and mice treated with α1-AC (bar 3) but not in mice treated with α2-AP (bar 2). n = 9; *P < 0.01. (B) Plasmin activity assay showed a significant reduction of tissue plasmin activity in the α2-AP–treated mice (bar 2) as compared with that in the PBS-treated (bar 1) and α1-AC–treated mice (bar 3). n = 8 for each group; **P < 0.001. (C) Zymography assay detected an actMMP-9 band in the skin of mice treated with PBS (lane 1) and α1-AC (lane 3) but not in the skin of mice treated with α2-AP (lane 2). MMP colorimetric assay revealed a significant reduction of active MMP levels in the skin samples of α2-AP–treated mice (bar 2) as compared with those in the lesional skin samples of PBS- (bar 1) and α1-AC–treated mice (bar 3). n = 8; #P < 0.05.