Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients
Bullous pemphigoid (BP), the by far most frequent autoimmune subepidermal blistering disorder (AIBD), is characterized by the deposition of autoantibodies against BP180 (type XVII collagen; Col17) and BP230 as well as complement components at the dermal-epidermal junction (DEJ). The mechanisms of co...
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.942493/full |
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| author | Shirin Emtenani Maike M. Holtsche Richard Stahlkopf Daniel L. Seiler Timothy Burn Huiqing Liu Melissa Parker Kaan Yilmaz Hasan O. Dikmen Markus Huber Lang Christian D. Sadik Christian M. Karsten Nina van Beek Ralf J. Ludwig Ralf J. Ludwig Jörg Köhl Jörg Köhl Enno Schmidt Enno Schmidt |
| author_facet | Shirin Emtenani Maike M. Holtsche Richard Stahlkopf Daniel L. Seiler Timothy Burn Huiqing Liu Melissa Parker Kaan Yilmaz Hasan O. Dikmen Markus Huber Lang Christian D. Sadik Christian M. Karsten Nina van Beek Ralf J. Ludwig Ralf J. Ludwig Jörg Köhl Jörg Köhl Enno Schmidt Enno Schmidt |
| author_sort | Shirin Emtenani |
| collection | DOAJ |
| description | Bullous pemphigoid (BP), the by far most frequent autoimmune subepidermal blistering disorder (AIBD), is characterized by the deposition of autoantibodies against BP180 (type XVII collagen; Col17) and BP230 as well as complement components at the dermal-epidermal junction (DEJ). The mechanisms of complement activation in BP patients, including the generation of C5a and regulation of its two cognate C5aRs, i.e., C5aR1 and C5aR2, are incompletely understood. In this study, transcriptome analysis of perilesional and non-lesional skin biopsies of BP patients compared to site-, age-, and sex-matched controls showed an upregulated expression of C5AR1, C5AR2, CR1, and C3AR1 and other complement-associated genes in perilesional BP skin. Of note, increased expressions of C5AR2 and C3AR1 were also observed in non-lesional BP skin. Subsequently, double immunofluorescence (IF) staining revealed T cells and macrophages as the dominant cellular sources of C5aR1 in early lesions of BP patients, while C5aR2 mainly expressed on mast cells and eosinophils. In addition, systemic levels of various complement factors and associated molecules were measured in BP patients and controls. Significantly higher plasma levels of C3a, CD55, and mannose-binding lectin-pathway activity were found in BP patients compared to controls. Finally, the functional relevance of C5aR1 and C5aR2 in BP was explored by two in vitro assays. Specific inhibition of C5aR1, resulted in significantly reduced migration of human neutrophils toward the chemoattractant C5a, whereas stimulation of C5aR2 showed no effect. In contrast, the selective targeting of C5aR1 and/or C5aR2 had no effect on the release of reactive oxygen species (ROS) from Col17-anti-Col17 IgG immune complex-stimulated human leukocytes. Collectively, this study delineates a complex landscape of activated complement receptors, complement factors, and related molecules in early BP skin lesions. Our results corroborate findings in mouse models of pemphigoid diseases that the C5a/C5aR1 axis is pivotal for attracting inflammatory cells to the skin and substantiate our understanding of the C5a/C5aR1 axis in human BP. The broad expression of C5aRs on multiple cell types critical for BP pathogenesis call for clinical studies targeting this axis in BP and other complement-mediated AIBDs. |
| first_indexed | 2024-04-11T06:50:44Z |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T06:50:44Z |
| publishDate | 2022-11-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-e8cb36281fae4c35a6c0ba273e0850862022-12-22T04:39:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-11-011310.3389/fimmu.2022.942493942493Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patientsShirin Emtenani0Maike M. Holtsche1Richard Stahlkopf2Daniel L. Seiler3Timothy Burn4Huiqing Liu5Melissa Parker6Kaan Yilmaz7Hasan O. Dikmen8Markus Huber Lang9Christian D. Sadik10Christian M. Karsten11Nina van Beek12Ralf J. Ludwig13Ralf J. Ludwig14Jörg Köhl15Jörg Köhl16Enno Schmidt17Enno Schmidt18Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, GermanyDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyLübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, GermanyInstitute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, GermanyIncyte Research Institute, Wilmington, DE, United StatesIncyte Research Institute, Wilmington, DE, United StatesIncyte Research Institute, Wilmington, DE, United StatesDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyInstitute of Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, GermanyDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyInstitute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, GermanyDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyLübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, GermanyDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyInstitute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, GermanyDivision of Immunobiology, Cincinnati Children’s Hospital Medical Centre, University of Cincinnati College of Medicine, Cincinnati, OH, United StatesLübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, GermanyDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyBullous pemphigoid (BP), the by far most frequent autoimmune subepidermal blistering disorder (AIBD), is characterized by the deposition of autoantibodies against BP180 (type XVII collagen; Col17) and BP230 as well as complement components at the dermal-epidermal junction (DEJ). The mechanisms of complement activation in BP patients, including the generation of C5a and regulation of its two cognate C5aRs, i.e., C5aR1 and C5aR2, are incompletely understood. In this study, transcriptome analysis of perilesional and non-lesional skin biopsies of BP patients compared to site-, age-, and sex-matched controls showed an upregulated expression of C5AR1, C5AR2, CR1, and C3AR1 and other complement-associated genes in perilesional BP skin. Of note, increased expressions of C5AR2 and C3AR1 were also observed in non-lesional BP skin. Subsequently, double immunofluorescence (IF) staining revealed T cells and macrophages as the dominant cellular sources of C5aR1 in early lesions of BP patients, while C5aR2 mainly expressed on mast cells and eosinophils. In addition, systemic levels of various complement factors and associated molecules were measured in BP patients and controls. Significantly higher plasma levels of C3a, CD55, and mannose-binding lectin-pathway activity were found in BP patients compared to controls. Finally, the functional relevance of C5aR1 and C5aR2 in BP was explored by two in vitro assays. Specific inhibition of C5aR1, resulted in significantly reduced migration of human neutrophils toward the chemoattractant C5a, whereas stimulation of C5aR2 showed no effect. In contrast, the selective targeting of C5aR1 and/or C5aR2 had no effect on the release of reactive oxygen species (ROS) from Col17-anti-Col17 IgG immune complex-stimulated human leukocytes. Collectively, this study delineates a complex landscape of activated complement receptors, complement factors, and related molecules in early BP skin lesions. Our results corroborate findings in mouse models of pemphigoid diseases that the C5a/C5aR1 axis is pivotal for attracting inflammatory cells to the skin and substantiate our understanding of the C5a/C5aR1 axis in human BP. The broad expression of C5aRs on multiple cell types critical for BP pathogenesis call for clinical studies targeting this axis in BP and other complement-mediated AIBDs.https://www.frontiersin.org/articles/10.3389/fimmu.2022.942493/fullautoimmune blistering diseasebullous pemphigoidcomplement activationcomplement component 5a receptor (C5aR) 1/2neutrophilsC5a/C5aR axis |
| spellingShingle | Shirin Emtenani Maike M. Holtsche Richard Stahlkopf Daniel L. Seiler Timothy Burn Huiqing Liu Melissa Parker Kaan Yilmaz Hasan O. Dikmen Markus Huber Lang Christian D. Sadik Christian M. Karsten Nina van Beek Ralf J. Ludwig Ralf J. Ludwig Jörg Köhl Jörg Köhl Enno Schmidt Enno Schmidt Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients Frontiers in Immunology autoimmune blistering disease bullous pemphigoid complement activation complement component 5a receptor (C5aR) 1/2 neutrophils C5a/C5aR axis |
| title | Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients |
| title_full | Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients |
| title_fullStr | Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients |
| title_full_unstemmed | Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients |
| title_short | Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients |
| title_sort | differential expression of c5ar1 and c5ar2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients |
| topic | autoimmune blistering disease bullous pemphigoid complement activation complement component 5a receptor (C5aR) 1/2 neutrophils C5a/C5aR axis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.942493/full |
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