Systemic inflammation impairs human myelopoiesis and interferon I responses

Systemic inflammation (SI) plays a detrimental role in various conditions with high mortality rates[1][1]–[4][2]. SI manifests an acute hyperinflammation followed by long-lasting immunosuppression, increasing patients’ risks for secondary infections and impaired clinical outcomes[5][3]–[7][4]. Due to the extensive heterogeneity in SI etiology, the mechanisms governing these states are incompletely understood. Here, we characterized acute and late effects of lipopolysaccharide (LPS)-induced SI (LPS-SI[8][5]) on blood monocytes and bone marrow (BM) cells of healthy volunteers. Like clinical SI, LPS administration elicited a profound but transient acute response. Single-cell transcriptomic analysis of acute LPS-SI unveiled loss of BM monocytes and appearance of an inflammatory monocyte-like (i-Mono’s) population, expressing gene programs similar to early-stage sepsis patients[9][6]. In the ensuing late phase of LPS-SI, we observed reduced expression of interferon type I (IFN-I) responsive genes in monocytes and profound attenuation of in vivo response to a second LPS challenge. Furthermore, late LPS-SI led to impaired myelopoiesis with a loss of intermediate and non-classical monocytes. In accordance, we show compromised myelopoiesis also occurs in late-stage sepsis. Finally, IFNβ treatment reversed LPS-induced immunosuppression in monocytes. Our results reveal long-lasting effects of SI on myelopoiesis and substantiate the importance of IFN-I in the pathophysiology of SI-induced immunosuppression. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05570643 ### Funding Statement F.K. is supported by the Princess Maxima Center and ZonMW-TOP project 91-21-6061. C.R.M. is supported by the Princess Maxima Center and the European Unions Horizon 2020 Skłodowska-Curie Actions (project AiPBAND) under grant #764281. W.M. is supported by the Italian National Operational Programme on Research 2014-2020 (PON AIM 1859703-2). H.G.S. is supported by the Princess Maxima Center and Kika (Kinderen Kankervrij). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the local ethics committee (CMO Arnhem-Nijmegen, The Netherlands, reference nos NL61136.091.17 and 2017-3337). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Bulk RNA-seq and scRNA-seq data for this study can be downloaded from GEO database () with the accession number: GSE212093. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-7 [5]: #ref-8 [6]: #ref-9