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Front. Immunol. | doi: 10.3389/fimmu.2018.02685

Sepsis Induces a Long-Lasting State of Trained Immunity in Bone Marrow Monocytes

 Katharina Bomas1,  Judith Schenz1, Isabella Sztwiertnia1,  Dominik Schaack1, Markus A. Weigand1 and  Florian Uhle1*
  • 1Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Germany

Innate immune memory describes the functional reprogramming of innate immune cells after pathogen contact, leading to either an improved (trained immunity) or a diminished (immune tolerance) response to a secondary stimulus. Immune tolerance or “sepsis-induced immunosuppression” is a typical hallmark of patients after sepsis survival, characterized by hypo-responsiveness of the host’s immune system. This condition renders the host vulnerable for a persisting infection or the occurrence of secondary, often opportunistic infections, along with an increased mortality rate. The mechanisms involved in the maintenance of this long-lasting condition are not examined yet.
Polymicrobial abdominal sepsis was induced in 12 week old male C57BL/6 mice by cecal ligation and puncture. Mice were euthanized three months after insult. Immune cell composition of the spleen and whole blood, as well as stem and progenitor cells of the bone marrow, were assessed by flow cytometry. Whole blood and bone marrow monocytes were stimulated with LPS and supernatant levels of TNF and IL-6 detected by ELISA. Furthermore, naïve bone marrow monocytes were analyzed for metabolic (Seahorse technology) and transcriptomic (RNA sequencing) changes.
Flow cytometric analysis revealed an increase of inflammatory monocytes and regulatory T cells in the spleen, whereby immune composition of whole blood kept unchanged. Granulocyte-monocyte progenitor cells are increased in sepsis survivors. Systemic cytokine response was unchanged after LPS challenge. In contrast, cytokine response of post-septic naïve bone marrow monocytes was increased. Metabolic analysis revealed enhanced glycolytic activity, whereas mitochondrial indices were not affected. In addition, RNA sequencing analysis of global gene expression in monocytes revealed a sustained signature of 367 differentially expressed genes.
We here demonstrate that sepsis via functional reprogramming of naïve bone marrow monocytes induces a cellular state of trained immunity, which might be counteracted depending on the compartmental localization of the cell. These findings shed new light on the complex aftermath of sepsis and open up a new pathophysiological framework in need for further research.

Keywords: SIRS, Cars, Immunosuppression, Metabolism, immune memory, trained immunity

Received: 31 Aug 2018; Accepted: 30 Oct 2018.

Edited by:

Thierry Roger, Lausanne University Hospital (CHUV), Switzerland

Reviewed by:

Paola Italiani, Italian National Research Council, Italy
Reinhard Wetzker, Friedrich-Schiller-Universität Jena, Germany  

Copyright: © 2018 Bomas, Schenz, Sztwiertnia, Schaack, Weigand and Uhle. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Florian Uhle, Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany, florian.uhle@med.uni-heidelberg.de