Monocytes enhance neutrophil‐induced blister formation in an ex vivo model of bullous pemphigoid

Graauw, Elisabeth de; Sitaru, Cassian; Horn, Michael P.; Borradori, Luca; Yousefi, Shída; Simon, Dagmar; Simon, Hans‐Uwe

doi:10.1111/all.13376

Cited by 30 publications

(28 citation statements)

References 55 publications

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“…Comparing the effect of two antibodies that deplete monocytes and neutrophils (anti-Ly6C/G) or only neutrophils (anti-Ly6G) suggests that the depletion of monocytes has an additional beneficial effect on experimental EBA ( 22 , 26 ). Moreover, monocytes are able to execute subepidermal cleft formation in an in vitro model of the disease ( 25 , 27 ). The roles of neutrophils and monocytes in pemphigoid diseases suggest that therapeutic principles targeting, like DMF, the recruitment of both neutrophils and monocytes into the skin may be superior to strategies solely targeting neutrophils.…”

Section: Discussionmentioning

confidence: 99%

The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation

et al. 2018

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The drug dimethyl fumarate (DMF) is in clinical use for the treatment of psoriasis and multiple sclerosis. In addition, it has recently been demonstrated to ameliorate skin pathology in mouse models of pemphigoid diseases, a group of autoimmune blistering diseases of the skin and mucous membranes. However, the mode of action of DMF in inflammatory skin diseases has remained elusive. Therefore, we have investigated here the mechanisms by which DMF improves skin pathology, using the antibody transfer model of bullous pemphigoid-like epidermolysis bullosa acquisita (EBA). Experimental EBA was induced by transfer of antibodies against collagen VII that triggered the infiltration of immune cells into the skin and led to inflammatory skin lesions. DMF treatment reduced the infiltration of neutrophils and monocytes into the skin explaining the improved disease outcome in DMF-treated animals. Upon ingestion, DMF is converted to monomethyl fumarate that activates the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, neutrophils and monocytes expressed Hca2. To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA2, we administered oral DMF to Hca2-deficient mice (Hca2−/−) and wild-type littermates (Hca2+/+) and induced EBA. DMF treatment ameliorated skin lesions in Hca2+/+ but not in Hca2−/− animals. These findings demonstrate that HCA2 is a molecular target of DMF treatment in EBA and suggest that HCA2 activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin.

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Section: Discussionmentioning

confidence: 99%

The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation

et al. 2018

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“…In an ex vivo skin model, eosinophils stimulated with IL-5 in the presence of BP serum caused a dermal-epidermal splitting resembling BP. This splitting was significantly decreased upon adding DNase I, suggesting that EET formation plays at least a partial role 90 . These observations make eosinophils interesting targets for therapy 91 .…”

Section: Eets and Nets In Bullous Pemphigoidmentioning

confidence: 96%

“…Bullous pemphigoid (BP) is an autoimmune blistering skin disease characterized by an activation of autoreactive B and T cells, the production of pathogenetically relevant autoantibodies directed against the hemidesmosomal proteins BP180 and BP230, and a prominent eosinophil infiltration in the skin 90 . It has been shown that in prebullous lesions, a small subgroup of eosinophils have formed EETs consisting of mtDNA associated with eosinophil granular proteins 26 .…”

Section: Eets and Nets In Bullous Pemphigoidmentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

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“…121 Dimethyl fumarate Immune complex deposition at the dermal epidermal junction (DEJ) in pemphigoid underlies the subsequent complement activation, neutrophil extravasation and proteolytic destruction in experimental models of pemphigoid and EBA. 15,[125][126][127][128] Dimethyl fumarate (DMF) is a prodrug utilized in the treatment of autoimmune disorders psoriasis and multiple sclerosis. 129,130 Its therapeutic effect is realized through downregulation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase and activation of nuclear factor erythroid 2-related factor 2 (NRF2) which stimulates expression of cytoprotective and antioxidant genes.…”

Section: Small Molecular Inhibitorsmentioning

confidence: 99%

“…Immune complex deposition at the dermal epidermal junction (DEJ) in pemphigoid underlies the subsequent complement activation, neutrophil extravasation and proteolytic destruction in experimental models of pemphigoid and EBA . Dimethyl fumarate (DMF) is a prodrug utilized in the treatment of autoimmune disorders psoriasis and multiple sclerosis .…”

Section: Evolving Therapeutic Targetsmentioning

confidence: 99%

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Kridin

Kowalski

Kneiber

et al. 2019

Acad Dermatol Venereol

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Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B‐cell depletion, T‐regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

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Monocytes enhance neutrophil‐induced blister formation in an ex vivo model of bullous pemphigoid

Cited by 30 publications

References 55 publications

The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation

The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation

In vivo evidence for extracellular DNA trap formation

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

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