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. 2024 Nov 7;31(11):1630-1649.e8.
doi: 10.1016/j.stem.2024.09.010. Epub 2024 Oct 15.

A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice

Taylor S Mills  1 , Bailee Kain  2 , Matt A Burchill  3 , Etienne Danis  4 , Erin D Lucas  5 , Rachel Culp-Hill  6 , Courtney M Cowan  1 , Wolfgang E Schleicher  7 , Sweta B Patel  7 , Brandon T Tran  2 , Ruoqiong Cao  2 , Andrew Goodspeed  4 , Sarah Ferrara  8 , Shaun Bevers  6 , Beth A Jirón Tamburini  9 , James R Roede  10 , Angelo D'Alessandro  6 , Katherine Y King  11 , Eric M Pietras  12
Affiliations

A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice

Taylor S Mills et al. Cell Stem Cell. .

Abstract

Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.

Keywords: autoimmune disease; bone marrow-derived macrophage; hematopoietic stem cell; inflammation; metabolism; trained immunity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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