학술논문
Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology
Document Type
Article
Author
Gullotta, Giorgia Serena; De Feo, Donatella; Friebel, Ekaterina; Semerano, Aurora; Scotti, Giulia Maria; Bergamaschi, Andrea; Butti, Erica; Brambilla, Elena; Genchi, Angela; Capotondo, Alessia; Gallizioli, Mattia; Coviello, Simona; Piccoli, Marco; Vigo, Tiziana; Della Valle, Patrizia; Ronchi, Paola; Comi, Giancarlo; D’Angelo, Armando; Maugeri, Norma; Roveri, Luisa; Uccelli, Antonio; Becher, Burkhard; Martino, Gianvito; Bacigaluppi, Marco
Source
Nature Immunology; 20230101, Issue: Preprints p1-16, 16p
Subject
Language
ISSN
15292908; 15292916
Abstract
Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101+CD62Llomature and CD177hiCD101loCD62Lloand CD177loCD101loCD62Lhiimmature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62Lloneutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62Lloneutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.