RT Journal Article
SR Electronic
T1 Maturation, developmental site, and pathology dictate murine neutrophil function
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.21.453108
DO 10.1101/2021.07.21.453108
A1 John B. G. Mackey
A1 Amanda J. McFarlane
A1 Thomas Jamieson
A1 Rene Jackstadt
A1 Ximena L. Raffo-Iraolagoitia
A1 Judith Secklehner
A1 Xabier Cortes-Lavaud
A1 Frédéric Fercoq
A1 William Clarke
A1 Ann Hedley
A1 Kathryn Gilroy
A1 Sergio Lilla
A1 Juho Vuononvirta
A1 Gerard J. Graham
A1 Katia De Filippo
A1 Daniel J. Murphy
A1 Colin W. Steele
A1 Jim C. Norman
A1 Thomas G. Bird
A1 Derek A. Mann
A1 Jennifer P. Morton
A1 Sara Zanivan
A1 Owen J. Sansom
A1 Leo M. Carlin
YR 2021
UL http://biorxiv.org/content/early/2021/07/28/2021.07.21.453108.abstract
AB Neutrophils have been implicated in poor outcomes in cancer and severe inflammation. We found that neutrophils expressing intermediate levels of Ly6G (Ly6GInt) were present in mouse cancer models and more abundant in those with high rates of spontaneous metastasis. Maturation, age, tissue localization and functional capacity all drive neutrophil heterogeneity. Recent studies have proposed various markers to distinguish between these heterogeneous sub-populations; however, these markers are limited to specific models of inflammation and cancer. Here, we identify and define Ly6G expression level as a robust and reliable marker to distinguish neutrophils at different stages of maturation. Ly6GInt neutrophils were bona fide ‘immature neutrophils’ with reduced immune regulatory and adhesion capacity. Whereas the bone marrow is a more recognised site of granulopoiesis, the spleen also produces neutrophils in homeostasis and cancer. Strikingly, neutrophils matured faster in the spleen than in the bone marrow with unique transcriptional profiles. We propose that developmental origin is critical in neutrophil identity and postulate that neutrophils that develop in the spleen supplement the bone marrow by providing an intermediate more mature reserve before emergency haematopoiesis.Competing Interest StatementDAM is a paid director and shareholder of Fibrofind limited. DJM receives research funding from Puma Bio-technology and Merck. OJS and TGB receive research funding from AstraZeneca.