Featured Publication in Focus: Recognition and control of neutrophil extracellular trap formation by MICL
Sep 17 , 2024
Authors:
Mariano Malamud, Lauren Whitehead, Alasdair McIntosh, Fabio Colella, Anke J. Roelofs, Takato Kusakabe, Ivy M. Dambuza, Annie Phillips-Brookes, Fabián Salazar, Federico Perez, Romey Shoesmith, Przemyslaw Zakrzewski, Emily A. Sey, Cecilia Rodrigues, Petruta L. Morvay, Pierre Redelinghuys, Tina Bedekovic, Maria J. G. Fernandes, Ruqayyah Almizraq, Donald R. Branch, Borko Amulic, Jamie Harvey, Diane Stewart, Raif Yuecel, Delyth M. Reid, Alex McConnachie, Matthew C. Pickering, Marina Botto, Iliyan D. Iliev, Iain B. McInnes, Cosimo De Bari, Janet A. Willment & Gordon D. Brown
MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom.
nature. 2024
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Product referenced:
Catalogue # CIA-MAB-2C
ArthritoMab™ Antibody Cocktail for C57BL/6, TG, 50 mg
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ABSTRACT
Regulation of neutrophil activation is critical for disease control. Neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and neutrophil-derived proteins, are formed following pro-inflammatory signals; however, if this process is uncontrolled, NETs contribute to disease pathogenesis, exacerbating inflammation and host tissue damage1,2. Here we show that myeloid inhibitory C-type lectin-like (MICL), an inhibitory C-type lectin receptor, directly recognizes DNA in NETs; this interaction is vital to regulate neutrophil activation. Loss or inhibition of MICL functionality leads to uncontrolled NET formation through the ROS–PAD4 pathway and the development of an auto-inflammatory feedback loop. We show that in the context of rheumatoid arthritis, such dysregulation leads to exacerbated pathology in both mouse models and in human patients, where autoantibodies to MICL inhibit key functions of this receptor. Of note, we also detect similarly inhibitory anti-MICL autoantibodies in patients with other diseases linked to aberrant NET formation, including lupus and severe COVID-19. By contrast, dysregulation of NET release is protective during systemic infection with the fungal pathogen Aspergillus fumigatus. Together, we show that the recognition of NETs by MICL represents a fundamental autoregulatory pathway that controls neutrophil activity and NET formation.
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