Interferon-sensitized hematopoietic progenitors dynamically alter organismal immunity [scRNA-seq]

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 IFNα. 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. 8-week old female, C57BL/6J mice were treated topically with imiquimod (post-inflamed; PI) or petrolium jelly (as control) for 7 days. Mice were then allowed to recover for 23 more days, at which point animals were fed a Western-Diet for 1 or 4 weeks. Mice were then euthanized and bone marrow harvested. LSK (Lin-/Sca+/Kit+) cells were flow-sorted and single cell RNA-seq performed.