CD98 defines a metabolically flexible, proinflammatory subset of low-density neutrophils in systemic lupus erythematosus

Martin, KR; Day, JA; Hansen, JA; D&#39;Silva, DB; Wong, HL; Garnham, A; Sandow, JJ; Nijagal, B; Wilson, N; Wicks, IP

Author(s): Martin, KR; Day, JA; Hansen, JA; D'Silva, DB; Wong, HL; Garnham, A; Sandow, JJ; Nijagal, B; Wilson, N; Wicks, IP;
Details: Publication Year 2023-01,Volume 13,Issue #1,Page e1150
Journal Title: Clinical and Translational Medicine
Abstract: BACKGROUND: Low-density neutrophils (LDN) are a distinct subset of neutrophils rarely detected in healthy people but appear in the blood of patients with autoimmune diseases, including systemic lupus erythematosus (SLE), and are mobilised in response to granulocyte colony-stimulating factor (G-CSF). The aim of this study was to identify novel mechanisms responsible for the pathogenic capacity of LDN in SLE. METHODS: Neutrophils were isolated from donors treated with G-CSF, and whole-cell proteomic analysis was performed on LDN and normal-density neutrophils. RESULTS: CD98 is significantly upregulated in LDN from G-CSF donors and defines a subset of LDN within the blood of SLE patients. CD98 is a transmembrane protein that dimerises with L-type amino acid transporters. We show that CD98 is responsible for the increased bioenergetic capacity of LDN. CD98 on LDN mediates the uptake of essential amino acids that are used by mitochondria to produce adenosine triphosphate, especially in the absence of glucose. Inhibition of CD98 reduces the metabolic flexibility of this population, which may limit their pathogenic capacity. CD98(+) LDN produce more proinflammatory cytokines and chemokines than their normal density counterparts and are resistant to apoptosis, which may also contribute to tissue inflammation and end organ damage in SLE. CONCLUSIONS: CD98 provides a phenotypic marker for LDN that facilitates identification of this population without density-gradient separation and represents a novel therapeutic target to limit its pathogenic capacity.
Publisher: Wiley
Keywords: Humans; Neutrophils/metabolismProteomics; Lupus Erythematosus, Systemic; Cytokines/metabolism; Granulocyte Colony-Stimulating Factor/metabolism; Cd98; granulocyte colony-stimulating factor; low-density neutrophils; systemic lupus erythematosus
Research Division(s): Inflammation; Advanced Technology And Biology; Bioinformatics
PubMed ID: 36653319
Publisher's Version: https://doi.org/10.1002/ctm2.1150
Open Access at Publisher's Site: https://doi.org/10.1002/ctm2.1150
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Clinical Translational Med - 2023 - Martin - CD98 defines a metabolically flexible proinflammatory subset of low‐density.pdf - (3.16MB, application/pdf)

Creation Date: 2023-02-27 10:36:25

Last Modified: 2023-03-06 01:45:47