A critical role for neutrophil elastase in experimental bullous pemphigoid

Li, Zhi; Shapiro, Steven D.; Zhou, Xigeng; Twining, Sally S.; Senior, Robert M.; Giudice, George J.; Fairley, Janet A.; Díaz, Luis A.

doi:10.1172/jci3693

Cited by 178 publications

(133 citation statements)

References 59 publications

(56 reference statements)

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“…This finding indicates an alternative scenario for the processing of the extracellular IL-1b precursor. Because blockade of IL-1 function in both EBA models led to incomplete inhibition of skin blistering, and lack of caspase-1/11 expression in mice showed little to no impact on blister formation, it is tempting to speculate that neutrophil-derived serine proteases (such as neutrophil elastase, proteinase-3, and cathepsin G) (37,38) cleave to the IL-1b precursor and control IL-1b protein expression.…”

Section: Discussionmentioning

confidence: 99%

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Sadeghi

Lockmann

Hund

et al. 2015

The Journal of Immunology

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Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1β in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1α and IL-1β expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R–deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti–IL-1β. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R–deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1–stimulated, but not on TNF-α–stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11–deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti–IL-1β in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs.

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Section: Discussionmentioning

confidence: 99%

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Sadeghi

Lockmann

Hund

et al. 2015

The Journal of Immunology

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“…In a murine model of the blistering skin disease bullous pemphigoid, passive transfer of antibodies against the hemidesmosomal protein BP180 causes an acute inflammatory reaction in which neutrophils migrate to the injection site and effect dermal-epidermal separation. NE is the most important enzyme in this model, with NE-deficient mice failing to form blisters (37). Although NE has been shown to cleave the hemidesmosomal protein BP180 both in vitro and in vivo (37), it is likely that NE-mediated cleavage of laminin-332, another structural component of hemidesmosomes connecting the epithelium to the basement membrane, contributes to blister formation in this model.…”

Section: Discussionmentioning

confidence: 88%

“…NE is the most important enzyme in this model, with NE-deficient mice failing to form blisters (37). Although NE has been shown to cleave the hemidesmosomal protein BP180 both in vitro and in vivo (37), it is likely that NE-mediated cleavage of laminin-332, another structural component of hemidesmosomes connecting the epithelium to the basement membrane, contributes to blister formation in this model. Similarly, leukocyte-medi-ated dermal-epidermal detachment can be elicited in human skin cryosections using BP180 auto-antibodies derived from patients with bullous pemphigoid, and selective inhibition of NE in this model suppresses this separation (57).…”

Section: Discussionmentioning

confidence: 88%

“…However, the biological significance of this is unknown because laminin-111 is not present in most adult tissues (32)(33)(34). BP180 (collagen XVII), a cell surface structural component of hemidesmosomes, contains a collagenous ectodomain that can be shed by members of the ADAMs protease family (35,36) and by NE (37,38). This ectodomain has been shown to be chemotactic for squamous cell carcinoma cells but not for normal keratinocytes, involving the ␣IIB integrin that is present on the tumor cells but not present on normal keratinocytes (39).…”

Section: Discussionmentioning

confidence: 99%

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Neutrophil Elastase Cleaves Laminin-332 (Laminin-5) Generating Peptides That Are Chemotactic for Neutrophils

Mydel

Shipley

Adair-Kirk

et al. 2008

Journal of Biological Chemistry

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Proteolytic processing of laminin-332 by matrix metalloproteinase (MMP)-2 and MMP-14 has been shown to yield fragments that are promigratory for epithelial cells. During acute and chronic inflammation, proteases are elaborated by neutrophils and macrophages that can degrade basement membranes. We investigated the susceptibility of laminin-332 to degradation by the following neutrophil and macrophage proteases: neutrophil elastase (NE), cathepsin G, proteinase-3, and MMPs-2, -8, -9, and -12. Protease-specific differences were seen in the capacity to cleave the individual chains of laminin-332. NE and MMP-12 showed the greatest activity toward the ␥2 chain, generating a fragment similar in size to the ␥2x fragment generated by MMP-2. The digestion pattern of laminin-332 by degranulated neutrophils was nearly identical to that generated with NE alone. Digestion by supernatants of degranulated neutrophils was blocked by an inhibitor of NE, and NE-deficient neutrophils were essentially unable to digest laminin-332, suggesting that NE is the major neutrophil-derived protease that degrades laminin-332. In vivo, laminin ␥2 fragments were found in the bronchoalveolar lavage fluid of wild-type mice treated with lipopolysaccharide, whereas that obtained from NE-deficient mice showed a different cleavage pattern. In addition, NE cleaved a synthetic peptide derived from the region of human laminin ␥2 containing the MMP-2 cleavage site, suggesting that NE may generate laminin-332 fragments that are also promigratory. Both laminin-332 fragments generated by NE digestion and NE-digested laminin ␥2 peptide were found to be chemotactic for neutrophils. Collectively, these data suggest that degradation of laminin-332 by NE generates fragments with important biological activities.Laminins are heterotrimeric proteins composed of ␣, ␤, and ␥ chains that are essential components of all basement membranes. Five ␣, four ␤, and three ␥ chains have been identified, which associate to form at least 15 laminin isoforms (1). Laminin-332 (formerly designated laminin-5) is composed of the ␣3, ␤3, and ␥2 chains and is a critical adhesive component of hemidesmosomes, specialized basement membrane structures underlying certain epithelia (2). Mutations of the LAMA3 (␣3), LAMB3 (␤3), or LAMC2 (␥2) genes result in the severe blistering disease epidermolysis bullosa (3, 4). Laminin-332 is presumably an essential laminin, as mice lacking expression of the ␥2 chain, which is unique to laminin-332, die a few days after birth (5).The ␣3, ␤3, and ␥2 chains are thought to self-associate via a central coiled-coil domain structure, with the short N-terminal arms of each extending from the coiled region to form a cruciform structure. Additionally, the C terminus of the ␣3 chain extends beyond the coiled region exposing five large globular (LG) 2 domains that are important in modulating the phenotype of attached cells. The unprocessed form of the ␣3 chain is thought to bind the ␣3␤1 integrin via the LG2 and LG3 domains, facilitating haptotactic migration of mu...

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“…Mouse models deficient in NE or MMP-9 are resistant to the disease [51,52]. In early blister formation, MMP-9 is predominantly activated by plasmin, which is formed by the tissue plasminogen activator (tPA) and/or urokinase plasminogen activator (uPA)-mediated degradation of plasminogen.…”

Section: Role Of Proteolytic Enzymesmentioning

confidence: 99%

Bullous Pemphigoid, Mucous Membrane Pemphigoid and Pemphigus Vulgaris: An Update on Pathobiology

Okon

Werth

2014

Curr Oral Health Rep

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A critical role for neutrophil elastase in experimental bullous pemphigoid

Cited by 178 publications

References 59 publications

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Caspase-1–Independent IL-1 Release Mediates Blister Formation in Autoantibody-Induced Tissue Injury through Modulation of Endothelial Adhesion Molecules

Neutrophil Elastase Cleaves Laminin-332 (Laminin-5) Generating Peptides That Are Chemotactic for Neutrophils

Bullous Pemphigoid, Mucous Membrane Pemphigoid and Pemphigus Vulgaris: An Update on Pathobiology

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