Interferon-sensitized hematopoietic progenitors dynamically alter organismal immunity

Guillamot, M.; Subudhi, I.; Paraskevopoulou, V.; Prystupa, A.; Sidhu, I.; Yeaton, A.; Laskou, M.; Hannemann, C.; Donahoe, C.; Wiseman, D.; Aifantis, I.; Naik, S.; Weinstock, A.

doi:10.1101/2024.04.24.590828

bioRxiv · 10.1101/2024.04.24.590828

Interferon-sensitized hematopoietic progenitors dynamically alter organismal immunity

Guillamot, M.·Subudhi, I.·Paraskevopoulou, V.·Prystupa, A.·Sidhu, I.·Yeaton, A.·Laskou, M.·Hannemann, C.·Donahoe, C.·Wiseman, D.·Aifantis, I.·Naik, S.·Weinstock, A.

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Abstract

Inflammation has enduring impacts on organismal immunity. However, the precise mechanisms by which tissue-restricted inflammation conditions systemic responses are poorly understood. Here, we leveraged a highly compartmentalized model of skin inflammation and identified a surprising type I interferon (IFN)- mediated activation of hematopoietic stem/progenitor cells (HSPCs) that results in profound changes to systemic host responses. Post-inflamed mice were protected from atherosclerosis and had worse outcomes following influenza virus infection. This IFN-mediated HSPC modulation was dependent on IFNAR signaling and could be recapitulated with the administration of recombinant IFN. Importantly, the transfer of post-inflamed HSPCs was sufficient to transmit the immune suppression phenotype. IFN modulation of HSPCs was rooted both in long-term changes in chromatin accessibility and the emergence of an IFN- responsive functional state from multiple progenitor populations. Collectively, our data reveal the profound and enduring effect of transient inflammation and more specifically type I IFN signaling and set the stage for a more nuanced understanding of HSPC functional modulation by peripheral immune signals.

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Guillamot, M., Subudhi, I., Paraskevopoulou, V., Prystupa, A., Sidhu, I., Yeaton, A., Laskou, M., Hannemann, C., Donahoe, C., Wiseman, D., Aifantis, I., Naik, S., Weinstock, A.. 2024-04-28. Interferon-sensitized hematopoietic progenitors dynamically alter organismal immunity. https://doi.org/10.1101/2024.04.24.590828

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