Raphaël Coscas1, Sebastien Dupont2, Sacha Mussot3, Liliane Louedec2, Harry Etienne2, Marion Morvan2, Gilles Chiocchia4, Ziad Massy5, Marie-Paule Jacob2, Jean-Baptiste Michel2. 1. UMR 1148, Inserm Paris 7, Denis Diderot University, Xavier Bichat Hospital, Paris, France; UMR 1173, Inserm Paris 11, Faculty of Health Sciences Simone Veil, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University, Montigny-le-Bretonneux, France; Department of Vascular Surgery, Ambroise Paré University Hospital, AP-HP, Boulogne-Billancourt, France; UMR 1018, Inserm Paris 11, CESP, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University, Paul Brousse Hospital, Villejuif, France. Electronic address: rcoscas@gmail.com. 2. UMR 1148, Inserm Paris 7, Denis Diderot University, Xavier Bichat Hospital, Paris, France. 3. Department of Thoracic Surgery, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France. 4. UMR 1173, Inserm Paris 11, Faculty of Health Sciences Simone Veil, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University, Montigny-le-Bretonneux, France. 5. UMR 1018, Inserm Paris 11, CESP, Versailles Saint-Quentin-en-Yvelines University, Paris-Saclay University, Paul Brousse Hospital, Villejuif, France; Department of Nephrology, Ambroise Paré University Hospital, AP-HP, Boulogne-Billancourt, France.
Abstract
BACKGROUND: Recent evidence suggests that adaptive immunity develops during abdominal aortic aneurysm evolution. Uncertainties remain about the antigens implicated and their role in inducing rupture. Because antigens from the extracellular matrix (ECM) have been suspected, the aim of this experimental study was to characterize the role of adaptive immunity directed against antigens from the aortic ECM. METHODS: In a first step, an experimental model of abdominal aortic aneurysm rupture based on adaptive immunity against the ECM was developed and characterized. Forty 4-week-old male Lewis rats were divided into two groups. In the ECM group (n = 20), rats were presensitized against the guinea pig aortic ECM before implantation of a decellularized aortic xenograft (DAX). In the control group (n = 20), rats were not presensitized before DAX implantation. In each group, half the rats were sacrificed at day 3 to analyze early mechanisms involved after DAX implantation. In a second step, we aimed to assess which ECM component was most efficient in inducing rupture. For this purpose, the nonfibrillar and fibrillar ECM components were sequentially extracted from the guinea pig aortic wall. Forty Lewis rats were then divided into four groups. Each group was presensitized against one ECM component (structural glycoproteins and proteoglycans, collagen, elastin alone, and elastin-associated glycoproteins) before DAX implantation. Apart from those that experienced rupture, rats were sacrificed at day 21. Xenografts were harvested for histologic, immunofluorescence, and conditioned medium analyses. RESULTS: In total, early aortic rupture occurred in 80% of the ECM group vs 0% of the control group (P < .001). In the ECM group, major circumferential immunoglobulin deposits were observed in combination with the C3 complement fraction, without cell infiltration. Conditioned medium analysis revealed that matrix metalloproteinase 9 and myeloperoxidase levels and elastase activities were significantly increased in this group. Immunofluorescence analysis demonstrated that myeloperoxidase co-localized with tissue-free DNA and histone H4, highlighting local neutrophil activation and formation of neutrophil extracellular traps. Following differential presensitization, it appeared that rats presensitized against structural glycoproteins and proteoglycans were significantly more susceptible to rupture after DAX implantation. CONCLUSIONS: Stimulating adaptive immunity against the aortic ECM, especially structural glycoproteins and proteoglycans, triggers rupture after DAX implantation. Further studies are needed to assess the precise proteins involved.
BACKGROUND: Recent evidence suggests that adaptive immunity develops during abdominal aortic aneurysm evolution. Uncertainties remain about the antigens implicated and their role in inducing rupture. Because antigens from the extracellular matrix (ECM) have been suspected, the aim of this experimental study was to characterize the role of adaptive immunity directed against antigens from the aortic ECM. METHODS: In a first step, an experimental model of abdominal aortic aneurysm rupture based on adaptive immunity against the ECM was developed and characterized. Forty 4-week-old male Lewis rats were divided into two groups. In the ECM group (n = 20), rats were presensitized against the guinea pig aortic ECM before implantation of a decellularized aortic xenograft (DAX). In the control group (n = 20), rats were not presensitized before DAX implantation. In each group, half the rats were sacrificed at day 3 to analyze early mechanisms involved after DAX implantation. In a second step, we aimed to assess which ECM component was most efficient in inducing rupture. For this purpose, the nonfibrillar and fibrillar ECM components were sequentially extracted from the guinea pig aortic wall. Forty Lewis rats were then divided into four groups. Each group was presensitized against one ECM component (structural glycoproteins and proteoglycans, collagen, elastin alone, and elastin-associated glycoproteins) before DAX implantation. Apart from those that experienced rupture, rats were sacrificed at day 21. Xenografts were harvested for histologic, immunofluorescence, and conditioned medium analyses. RESULTS: In total, early aortic rupture occurred in 80% of the ECM group vs 0% of the control group (P < .001). In the ECM group, major circumferential immunoglobulin deposits were observed in combination with the C3 complement fraction, without cell infiltration. Conditioned medium analysis revealed that matrix metalloproteinase 9 and myeloperoxidase levels and elastase activities were significantly increased in this group. Immunofluorescence analysis demonstrated that myeloperoxidase co-localized with tissue-free DNA and histone H4, highlighting local neutrophil activation and formation of neutrophil extracellular traps. Following differential presensitization, it appeared that rats presensitized against structural glycoproteins and proteoglycans were significantly more susceptible to rupture after DAX implantation. CONCLUSIONS: Stimulating adaptive immunity against the aortic ECM, especially structural glycoproteins and proteoglycans, triggers rupture after DAX implantation. Further studies are needed to assess the precise proteins involved.
Authors: Branislav Zagrapan; Wolf Eilenberg; Andreas Scheuba; Johannes Klopf; Annika Brandau; Julia Story; Katharina Dosch; Hubert Hayden; Christoph M Domenig; Lukas Fuchs; Rüdiger Schernthaner; Robin Ristl; Ihor Huk; Christoph Neumayer; Christine Brostjan Journal: J Cardiovasc Transl Res Date: 2020-12-17 Impact factor: 4.132
Authors: Laura Lopez-Sanz; Susana Bernal; Luna Jimenez-Castilla; Ignacio Prieto; Sara La Manna; Sergio Gomez-Lopez; Luis Miguel Blanco-Colio; Jesus Egido; Jose Luis Martin-Ventura; Carmen Gomez-Guerrero Journal: Clin Transl Med Date: 2021-07