Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression.

Jibril, Aisha, Hellmich, Charlotte, Wojtowicz, Edyta, Hampton, Katherine, Maynard, Rebecca S., De Silva, Ravindu, Fowler-Shorten, Dominic J, Mistry, Jayna J., Moore, Jamie A, Bowles, Kristian M. ORCID: and Rushworth, Stuart A. (2023) Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression. Blood. ISSN 0006-4971

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Mitochondrial damage-associated molecular patterns (mtDAMPs) include proteins, lipids, metabolites and DNA and have various context specific immunoregulatory functions. Cell-free mitochondrial DNA (mtDNA) is recognised via pattern recognition receptors and is a potent activator of the innate immune system. Cell-free mtDNA is elevated in the circulation of trauma and cancer patients, however the functional consequences of elevated mtDNA are largely undefined. Multiple myeloma (MM) relies upon cellular interactions within the bone marrow (BM) microenvironment for survival and progression. Here, using in-vivo models, we describe the role of MM cell derived mtDAMPs in the pro-tumoral BM microenvironment, and the mechanism and functional consequence of mtDAMPs in myeloma disease progression. Initially, we identified elevated levels of mtDNA in the peripheral blood serum of MM patients compared to healthy controls. Using the MM1S cells engrafted into NSG mice we established that elevated mtDNA was derived from MM cells. We further show that BM macrophages sense and respond to mtDAMPs through the STING pathway and inhibition of this pathway reduces MM tumor-burden in the KaLwRij-5TGM1 mouse model. Moreover, we found that MM derived mtDAMPs induced upregulation of chemokine signatures in BM macrophages and inhibition of this signature resulted in egress of MM cells from the BM. Here, we demonstrate that malignant plasma cells release mtDNA, a form of mtDAMPs, into the myeloma BM microenvironment, which in turn activates macrophages via STING signalling. We establish the functional role of these mtDAMP-activated macrophages in promoting disease progression and retaining MM cells in the pro-tumoral BM microenvironment.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 14 Mar 2023 11:30
Last Modified: 20 Mar 2023 01:14
DOI: 10.1182/blood.2022018711

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