Recognition and control of neutrophil extracellular trap formation by MICL

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 Bari, Janet A. Willment and Gordon D. Brown ()
Additional contact information
Mariano Malamud: University of Exeter
Lauren Whitehead: University of Aberdeen
Alasdair McIntosh: University of Glasgow
Fabio Colella: University of Aberdeen
Anke J. Roelofs: University of Aberdeen
Takato Kusakabe: Weill Cornell Medicine
Ivy M. Dambuza: University of Exeter
Annie Phillips-Brookes: University of Exeter
Fabián Salazar: University of Exeter
Federico Perez: Hospital for Sick Children
Romey Shoesmith: University of Exeter
Przemyslaw Zakrzewski: University of Bristol
Emily A. Sey: University of Exeter
Cecilia Rodrigues: University of Exeter
Petruta L. Morvay: University of Exeter
Pierre Redelinghuys: University of Aberdeen
Tina Bedekovic: University of Exeter
Maria J. G. Fernandes: Laval University
Ruqayyah Almizraq: Canadian Blood Services
Donald R. Branch: Canadian Blood Services
Borko Amulic: University of Bristol
Jamie Harvey: University of Exeter
Diane Stewart: University of Aberdeen
Raif Yuecel: University of Exeter
Delyth M. Reid: University of Aberdeen
Alex McConnachie: University of Glasgow
Matthew C. Pickering: Imperial College London
Marina Botto: Imperial College London
Iliyan D. Iliev: Weill Cornell Medicine
Iain B. McInnes: University of Glasgow
Cosimo Bari: University of Aberdeen
Janet A. Willment: University of Exeter
Gordon D. Brown: University of Exeter

Nature, 2024, vol. 633, issue 8029, 442-450

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07820-3

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