02271nas a2200253   4500000000100000008004100001260001200042653002300054653001200077653001500089653001400104653001700118653003000135100001100165700001100176700001100187700001000198700001200208700001000220245010400230490000800334520166100342022001402003       2023                            d  c09/202310aExpression profile10aleprosy10aMacrophage10aNude mice10aSchwann cell10aSingle cell transcriptome1 aShin S1 aChoi E1 aMoon S1 aLee S1 aChung Y1 aLee S00aLeprosy-specific subsets of macrophages and Schwann cells identified by single-cell RNA-sequencing.0 v2503 a<p>In Mycobacterium leprae (M. leprae)-infection, inflammatory cells' subsets and dynamics as well as the interactions with Schwann cells have remained elusive. We investigated individual cells in M. leprae-inoculated nude mice by single-cell RNA-sequencing (scRNA-seq). For macrophages, we dissected two M1-like subsets and five M2-like subsets, where lipid-associated signatures were pervasive in both M1-like and M2-like subsets. There were four macrophage trajectories showing: (i) pro-inflammatory (M1), (ii) lipid metabolism-related (M2), (iii) anti-inflammatory (M2), and (iv) interferon-stimulated gene-related (M2) fates. They displayed early divergence without ever rejoining along the paths, suggesting simultaneous or continuous stimuli for macrophage activation in leprosy. The scRNA-seq predicted Schwann cell-macrophage interactions (Notch1-Jag1, Plxnb1-Sema4d interactions). An immature Schwann cell subset showing Tfap2a expression was identified, indicating Schwann cell dedifferentiation in leprosy tissues. Expressions of Notch1, Jag1, Plxnb1, Sema4d, and Tfap2a were validated in mouse or human leprosy tissues by immunohistochemistry. We identified both pro-inflammatory and inflammation-resolution signatures, where lipid-associated signatures were pervasive to the macrophages, representing leprosy-specific macrophage states for prolonged and repeated episodes of inflammation and resolution. Our study identified refined molecular states and interactions of macrophages and Schwann cells, suggesting novel insights into the pathogenesis of unhealed inflammation with neuropathy and potential therapeutic targets for leprosy.</p>
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