Maturation, developmental site, and pathology dictate murine neutrophil function

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 localizati...

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Published inbioRxiv
Main Authors Mackey, John B G, Mcfarlane, Amanda J, Jamieson, Thomas, Jackstadt, Rene, Raffo-Iraolagoitia, Ximena L, Secklehner, Judith, Cortes-Lavaud, Xabier, Fercoq, Frederic, Clarke, William, Hedley, Ann, Gilroy, Kathryn, Lilla, Sergio, Vuononvirta, Juho, Graham, Gerard J, De Filippo, Katia, Murphy, Daniel J, Steele, Colin W, Norman, Jim C, Bird, Thomas G, Mann, Derek A, Morton, Jennifer P, Zanivan, Sara, Sansom, Owen J, Carlin, Leo M
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 28.07.2021
Subjects
Animal models
Bone marrow
Cancer
Granulopoiesis
Homeostasis
Inflammation
Leukocytes (neutrophilic)
Localization
Maturation
Metastases
Neutrophils
Research funding
Spleen
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Summary: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 Statement DAM 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. Footnotes * Accession code and funding information updated
DOI:10.1101/2021.07.21.453108