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bioRxiv · 10.1101/2025.05.23.655632

Tissue signatures of human macrophages during homeostasis and activation

Caron, D. P.·Specht, W. L.·Chen, D.·Wells, S. B.·Szabo, P. A.·Sims, P. A.·Farber, D. L.
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Abstract

Human macrophages (M{Phi}s) reside in tissues and develop tissue-specific identities. While studies in mice have identified molecular signatures for site-specific M{Phi} differentiation, we know less about the transcriptional profiles of human M{Phi}s in distinct sites, including mucosal tissues and lymphoid organs during homeostasis and activation. Here, we use multimodal single-cell sequencing and ex vivo stimulation assays to define tissue signatures for populations of human M{Phi}s isolated from lungs, small intestine, spleen, bone marrow, and lymph nodes obtained from individual organ donors. Our results reveal distinct tissue-adapted gene and protein profiles of metabolic, adhesion, and immune interaction pathways, which are specific to M{Phi}s and not monocytes isolated from the same sites. These signatures exhibit homology to murine M{Phi}s from the same sites. Tissue-adapted M{Phi}s remained responsive to polarizing cytokine stimuli ex vivo, with upregulation of expected transcripts and secreted proteins, while retaining tissue-specific profiles. Together, our findings show how human M{Phi} identity is coupled to their site of residence for mucosal and lymphoid organs and is intrinsically maintained during activation and polarization.

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Caron, D. P., Specht, W. L., Chen, D., Wells, S. B., Szabo, P. A., Sims, P. A., Farber, D. L.. 2025-05-28. Tissue signatures of human macrophages during homeostasis and activation. https://doi.org/10.1101/2025.05.23.655632

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