title: Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression.
abstract: Calpains are intracellular proteases that play a key role in inflammation/immunity. Rare studies show that they are partially externalized. However, the mechanism of this secretion and the functions of exteriorized calpains remain poorly understood. In this study, we found that mouse and human lymphocytes secreted calpains through an ABCA1-driven process. In turn, extracellular calpains inhibited IL-17A expression. We were able to attribute this function to a cleavage of the TLR2 extracellular domain, which prevented TLR2-induced transcription of molecules essential for IL-17A induction. Calpain exteriorization and TLR2 cleavage were critical for the control of IL-17A expression by low doses of IL-2. By using newly developed transgenic mice in which extracellular calpains are specifically inactivated, we provide evidence for the relevance of calpain externalization in vivo in regulating IL-17A expression and function in experimental sterile peritonitis and autoimmune arthritis, respectively. Thus, this study identifies calpain exteriorization as a potential target for immune modulation.
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France;
authors.forename: Joëlle
authors.initials: J
authors.lastname: Perez
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France;
authors.forename: Boris
authors.initials: B
authors.lastname: Dansou
authors.affiliation: UMR_S 1125, Université Paris 13, Sorbonne Paris Cité, F-93000 Bobigny, France; UMR_S 1125, INSERM, F-93000 Bobigny, France;
authors.forename: Roxane
authors.initials: R
authors.lastname: Hervé
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France;
authors.forename: Charlène
authors.initials: C
authors.lastname: Levi
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France; Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, F-75020 Paris, France;
authors.forename: Houda
authors.initials: H
authors.lastname: Tamouza
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.affiliation: École supérieure de physique et de chimie industrielles de la ville de Paris/Spectrométrie de masse biologique et protéomique, F 75014 Paris, France;
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Demey-Thomas
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France; Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, F-75020 Paris, France;
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Haymann
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France;
authors.forename: Lara
authors.initials: L
authors.lastname: Zafrani
authors.affiliation: UMR_S 959 and Immunologie-Immunopathologie-Immunothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75005 Paris, France; Biotherapy and Département Inflammation-Immunopathologie-Biothérapie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, F-75651 Paris, France; and.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.affiliation: UMR_S 1125, Université Paris 13, Sorbonne Paris Cité, F-93000 Bobigny, France; UMR_S 1125, INSERM, F-93000 Bobigny, France; Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Assistance Publique-Hôpitaux de Paris, F-93000 Bobigny, France.
authors.forename: Marie-Christophe
authors.initials: MC
authors.lastname: Boissier
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France; Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, F-75020 Paris, France;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.affiliation: UMR_S 1155 and Département Inflammation-Immunopathologie-Biothérapie, Université Pierre et Marie Curie Paris 06, Sorbonne Universités, F-75020 Paris, France; UMR_S 1155, INSERM, F-75020 Paris, France; Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, F-75020 Paris, France; laurent.baud@tnn.aphp.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental; D002154:Calpain / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D007376:Interleukin-2 / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; C508717:IL17A protein, human; C508594:IL2 protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D007376:Interleukin-2; D034741:RNA, Small Interfering; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D002154:Calpain