mTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome

Zhengping Huang, Xiaomeng You, Liang Chen, Yan Du, Kailey Brodeur, Hyuk Jee, Qiang Wang, Grace Linder, Roxane Darbousset, Pierre Cunin, Margaret H. Chang, Alexandra Wactor, Brian M. Wauford, Marc J. C. Todd, Kevin Wei, Ying Li, Anais Levescot, Yoichiro Iwakura, Virginia Pascual, Nicole E. Baldwin, Pierre Quartier, Tianwang Li, Maria T. Gianatasio, Robert P. Hasserjian, Lauren A. Henderson, David B. Sykes, Elizabeth D. Mellins, Scott W. Canna, Julia F. Charles, Peter A. Nigrovic () and Pui Y. Lee ()
Additional contact information
Zhengping Huang: Harvard Medical School
Xiaomeng You: Harvard Medical School
Liang Chen: Harvard Medical School
Yan Du: Harvard Medical School
Kailey Brodeur: Harvard Medical School
Hyuk Jee: Harvard Medical School
Qiang Wang: Harvard Medical School
Grace Linder: Children’s Hospital of Philadelphia
Roxane Darbousset: Harvard Medical School
Pierre Cunin: Harvard Medical School
Margaret H. Chang: Harvard Medical School
Alexandra Wactor: Harvard Medical School
Brian M. Wauford: Harvard Medical School
Marc J. C. Todd: Harvard Medical School
Kevin Wei: Harvard Medical School
Ying Li: Harvard Medical School
Anais Levescot: Université Paris Cité, Institut Imagine, INSERM UMR1163, Laboratory Intestinal Immunity
Yoichiro Iwakura: Tokyo University of Science
Virginia Pascual: Weill Cornell Medicine
Nicole E. Baldwin: Baylor Scott & White Research Institute
Pierre Quartier: Universite de Paris
Tianwang Li: Guangdong Second Provincial General Hospital
Maria T. Gianatasio: Mass General Brigham Healthcare Center - Salem Hospital
Robert P. Hasserjian: Harvard Medical School
Lauren A. Henderson: Harvard Medical School
David B. Sykes: Massachusetts General Hospital
Elizabeth D. Mellins: Stanford University
Scott W. Canna: Children’s Hospital of Philadelphia
Julia F. Charles: Harvard Medical School
Peter A. Nigrovic: Harvard Medical School
Pui Y. Lee: Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Still’s disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still’s disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still’s disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still’s disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still’s disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still’s disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still’s disease and macrophage activation syndrome.

Date: 2022
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DOI: 10.1038/s41467-022-34480-6

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