CD163 Expression Defines a Red Pulp Macrophage Subset Engaged in Crosstalk with Marginal Metallophilic Macrophages During Blood-Stage Malaria
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ABSTRACT: The spleen harbors distinct macrophage subsets that support circulatory homeostasis and initiate immune responses. Yet, the ontogeny and long-term dynamics of these populations remain incompletely understood. Here, we identify a transcriptionally and developmentally distinct CD163-expressing red pulp macrophage (CD163high RPM) population that arises from yolk sac progenitors and maintains CD163 expression under homeostatic conditions. Using fate-mapping models, we show that CD163- RPMs are progressively replenished by monocytes during ageing, whereas CD163high RPMs are rather self-maintaining and occupy a vascular-associated niche. During blood-stage malaria, CD163high RPMs are rapidly depleted and fail to recover despite clearance of parasitemia. Mechanistically, the loss of CD163 expression is driven by infection-induced hemolysis and iron depletion, not parasite persistence. Single-cell RNA sequencing reveals that CD163high RPMs act as dominant signaling hubs under steady state, but malaria disrupts these intercellular communication networks, including a previously unrecognized interaction with marginal metallophilic macrophages (MMMs). CD163 deficiency exacerbates structural disintegration of the marginal zone and selectively impairs MMM recovery, underscoring a CD163-dependent regulatory axis between RPMs and MMMs. This study provides a comprehensive ontogenetic and functional map of splenic macrophages, and reveals that the sustained loss of a specialized, yolk sac-derived CD163high RPM subset rewires splenic architecture and inter-macrophage crosstalk long after infection resolution.
ORGANISM(S): Mus musculus
PROVIDER: GSE303987 | GEO | 2026/07/28
REPOSITORIES: GEO
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