The Serpin α1-Proteinase Inhibitor Is a Critical Substrate for Gelatinase B/MMP-9 In Vivo

We have identified the key protein substrate of gelatinase B/MMP-9 (GB) that is cleaved in vivo during dermal–epidermal separation triggered by antibodies to the hemidesmosomal protein BP180 (collagen XVII, BPAG2). Mice deficient in either GB or neutrophil elastase (NE) are resistant to blister formation in response to these antibodies in a mouse model of the autoimmune disease bullous pemphigoid. Disease develops upon complementation of GB−/− mice with NE−/− neutrophils or NE−/− mice with GB−/− neutrophils. Only NE degrades BP180 and produces dermal–epidermal separation in vivo and in culture. Instead, GB acts upstream to regulates NE activity by inactivating α1-proteinase inhibitor (α1-PI). Excess NE produces lesions in GB−/− mice without cleaving α1-PI. Excess α1-PI phenocopies GB and NE deficiency in wild-type mice.