Diverse lung challenges elicit a conserved monocyte-to-macrophage differentiation blueprint

Iliakis, C.; T'Jonck, W.; Mouat, I. C.; Bankole, S.; Liang, J.; Jones, G.-R.; Kulikauskaite, J.; Burgess, M. O.; Janas, P.; Crotta, S.; Priestnall, S.; Suarez-Bonnet, A.; Schwarze, J.; Wack, A.; Bain, C. C.

doi:10.64898/2026.03.15.711867

bioRxiv · 10.64898/2026.03.15.711867

Diverse lung challenges elicit a conserved monocyte-to-macrophage differentiation blueprint

Iliakis, C.·T'Jonck, W.·Mouat, I. C.·Bankole, S.·Liang, J.·Jones, G.-R.·Kulikauskaite, J.·Burgess, M. O.·Janas, P.·Crotta, S.·Priestnall, S.·Suarez-Bonnet, A.·Schwarze, J.·Wack, A.·Bain, C. C.

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Abstract

Alveolar macrophages (AM) form a first line of defence to lung insults. These insults often lead to replacement of foetal-derived tissue-resident AMs (fAMs) by monocyte-derived AMs (mono-AMs) with different functionality, which impacts lung immunity long-term. However, whether these alterations are conserved or insult-specific is not well understood. Here, we show that respiratory syncytial virus (RSV) infection remodels the AM compartment long-term. We perform comparative analyses of fAMs and mono-AMs after RSV infection, influenza (IAV) infection and clodronate liposome administration to derive rules governing the functional and transcriptional changes in AM across insults. We identify a crucial tissue integration checkpoint of CD11b+ mono-AMs which involves acquisition of proliferative capacity and requires EGR2-mediated transcriptional rewiring. Mono-AMs elicited by RSV, influenza or clodronate liposomes have a hard-wired ontogeny-dependent stereotypical profile of transcription, metabolism and enhanced immunoreactivity despite a substantially different inflammatory environment during differentiation; accordingly, mono-AMs, whether elicited by infection or sterile depletion, protect from subsequent S. pneumoniae infection. By contrast, fAMs are more susceptible to subtle, context-dependent transcriptional alterations. Our findings highlight that long-term changes in the AM compartment show origin-dependent phenotypic divergence and that mono-AM integration follows a hard-wired trajectory fine-tuned by environmental factors.

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Iliakis, C., T'Jonck, W., Mouat, I. C., Bankole, S., Liang, J., Jones, G.-R., Kulikauskaite, J., Burgess, M. O., Janas, P., Crotta, S., Priestnall, S., Suarez-Bonnet, A., Schwarze, J., Wack, A., Bain, C. C.. 2026-03-17. Diverse lung challenges elicit a conserved monocyte-to-macrophage differentiation blueprint. https://doi.org/10.64898/2026.03.15.711867

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