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

Abstract

Innate immune memory describes the functional reprogramming of innate immune cells after pathogen contact, leading to either a boosted (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 3 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.

A Sustained Immune Response Supports Long-Term Antiviral Immune Priming in the Pacific Oyster, Crassostrea gigas

“…Little is known for the oyster and more generally for invertebrates, which lack the classical adaptive immune system (lymphocyte and immunoglobulinrelated), regarding the cellular and molecular carriers of immune priming. Epigenetic changes seem to be a prerequisite for trained innate immunity in mammals and a convergent feature of innate immune memory (50,51). Epigenetic changes in the vicinity of the promoters of candidate immune genes could explain, at least partially, how the baseline transcript expression is lastingly changed in response to priming.…”

Induction of Innate Immune Memory by Engineered Nanoparticles in Monocytes/Macrophages: From Hypothesis to Reality

“…Furthermore, sepsis is able to induce an inflammatory memory phenotype in bone marrow monocytes. Indeed, post-septic naïve bone marrow monocytes and blood monocytes isolated from mice showed an increased cytokine production when stimulated with LPS in vitro ( 51 ).…”

β-Glucan as Trained Immunity-Based Adjuvants for Rabies Vaccines in Dogs

“…β-(1-3)-glucan from Euglena gracilis was purchased from Sigma-Aldrich (Catalog number: 89862; batch: BCBZ6291). 0.5 ml of the suspension was injected at 5 mg/ml, for a dose of 2.5 mg/animal, a dose that was selected according to a review of several clinical studies performed with β-glucan injection ( 19 , 22 – 25 ).…”