Synergy between a plasminogen cascade and MMP-9 in autoimmune disease
Zhi Liu, Ning Li, Luis A. Diaz, Michael Shipley, Robert M. Senior, Zena Werb
Zhi Liu, Ning Li, Luis A. Diaz, Michael Shipley, Robert M. Senior, Zena Werb
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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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MC activation in Plg- and tuPA-deficient mice. WT, Plg–/–, and tuPA–/– m...
MC activation in Plg- and tuPA-deficient mice. WT, Plg–/–, and tuPA–/– mice were injected i.d. with pathogenic IgG (R530; 2.64 mg/g body weight). At 2 hours after injection, when MC degranulation reached the peak level, skin sections were stained with toluidine blue solution. (A–D) Toluidine blue staining showed similar degrees of MC degranulation in pathogenic IgG-injected WT and deficient mice. (E) The MCs in the dermis were counted and classified as degranulated (more than 10% of the granules exhibiting fusion or discharge) or normal (see Methods). There was no significant difference in MC degranulation among these mice (mean ± SEM). Arrows indicate MCs.