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 1

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The Plg/plasmin system is required for experimental BP. WT mice and mice...
The Plg/plasmin system is required for experimental BP. WT mice and mice deficient in different components of the Plg/plasmin system were injected i.d. with pathogenic anti-mBP180 IgG (R530) or control IgG and examined 12 hours later. (A–H) WT (A and B), tPA–/– (E), and uPA–/– (F), but not tuPA–/– (G) or Plg–/– (H) mice injected with pathogenic IgG developed subepidermal blisters. WT injected with control IgG showed no disease (C and D). Arrows indicate sites of basal keratinocytes. E, epidermis; D, dermis; V, blister vesicle. Magnification, ×200. Higher magnifications of H&E staining sections demonstrate infiltrating neutrophils in the dermis (insets). Arrowheads indicate neutrophils. Magnification, ×920. (I) Plasmin chromogenic assay showed significantly higher levels of plasmin activity in the lesional skin of WT (bar 1), tPA–/– (bar 3), and uPA–/– (bar 4) mice as compared with the nonlesional skin of control (bar 2), tuPA–/– (bar 5), and Plg–/– (bar 6) mice. Data shown are the mean ± SEM. n = 9 for each group; *P < 0.001 versus WT. (J) MPO activity assay at 12 hours after injection (black bars) showed significantly higher levels of PMN recruitment in the lesional skin of WT (bar 7), tPA–/– (bar 9), and uPA–/– (bar 10) mice as compared with tuPA–/– (bar 11) and Plg–/– (bar 12) mice. At 4 hours after injection (gray bars), all mice had similar numbers of infiltrating neutrophils. n = 9 for each group; *P < 0.001 versus WT.