Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

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 lymph...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2016-01, Vol.196 (1), p.168-181
Main Authors: Perez, Joëlle, Dansou, Boris, Hervé, Roxane, Levi, Charlène, Tamouza, Houda, Vandermeersch, Sophie, Demey-Thomas, Emmanuelle, Haymann, Jean-Philippe, Zafrani, Lara, Klatzmann, David, Boissier, Marie-Christophe, Letavernier, Emmanuel, Baud, Laurent
Format: Article
Language:English
Subjects:
Animals
Arthritis, Experimental
ATP Binding Cassette Transporter 1 - biosynthesis
ATP Binding Cassette Transporter 1 - genetics
Calpain - metabolism
Calpain - secretion
Cell Line
Cell Proliferation
Gene Expression Regulation
HEK293 Cells
Humans
Inflammation - immunology
Inflammation Mediators - immunology
Interleukin-17 - biosynthesis
Interleukin-17 - genetics
Interleukin-2 - therapeutic use
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neutrophils - immunology
RNA Interference
RNA, Small Interfering
Spleen - cytology
T-Lymphocytes - immunology
Toll-Like Receptor 2 - metabolism
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1500749