Sepsis has been identified by the World Health Organization (WHO) as a global health priority. There has been a tremendous effort to decipher underlying mechanisms responsible for organ failure and death, and to develop new treatments. Despite saving thousands of animals over the last three decades in multiple preclinical studies, no new effective drug has emerged that has clearly improved patient outcomes. In the present review, we analyze the reasons for this failure, focusing on the inclusion of inappropriate patients and the use of irrelevant animal models. We advocate against repeating the same mistakes and propose changes to the research paradigm. We discuss the long‐term consequences of surviving sepsis and, finally, list some putative approaches—both old and new—that could help save lives and improve survivorship.

Introduction: An effective immune response to severe bacterial infections requires a robust production of the innate immunity cells from hematopoietic stem and progenitor cells (HSPCs) in a process called emergency myelopoiesis. In sepsis, an altered immune response that leads to a failure of bacterial clearance is often observed. In this study, we aimed to evaluate the impact of sepsis on human HSPCs in the bone marrow (BM) microenvironment of humanized mice subjected to acute endotoxemia and polymicrobial sepsis. Methods: Humanized mice (hu-NSG) were generated by transplanting NOD.Cg-Prkdc/scidIL2rγ (NSG) mice with the human cord blood CD34⁺ cells. Eight weeks after the transplantation, hu-NSG mice were subjected to sepsis induced by endotoxemia—Escherichia coli lipopolysaccharide (LPS)—or by cecal ligation and puncture (CLP). Twenty-four hours later, HSPCs from BM were analyzed by flow cytometry and colony-forming unit (CFU) assay. CLP after inhibition of Notch signaling was also performed. The effects of LPS on the in vitro proliferation of CD34⁺ cells from human BM were tested by CellTrace Violet dye staining. Results: The expression of Toll-like receptor 4 receptor was present among engrafted human HSPCs. Both CLP and endotoxemia decreased (by 43 % and 37 %) cellularity of the BM. In addition, in both models, accumulation of early CD34⁺ CD38⁻ HSCs was observed, but the number of CD34⁺ CD38⁺ progenitors decreased. After CLP, there was a 1.5-fold increase of proliferating CD34⁺ CD38⁻Ki-67⁺ cells. Moreover, CFU assay revealed a depressed (by 75 % after LPS and by 50 % after CLP) production of human hematopoietic colonies from the BM of septic mice. In contrast, in vitro LPS stimulated differentiation of CD34⁺ CD38⁻ HSCs but did not induce proliferation of these cells in contrast to the CD34⁺ CD38⁺ progenitors. CLP sepsis modulated the BM microenvironment by upregulation of Jagged-1 expression on non-hematopoietic cells, and the proliferation of HSCs was Notch-dependent. Conclusions: CLP sepsis and endotoxemia induced a similar expansion and proliferation of early HSCs in the BM, while committed progenitors decreased. It is suggestive that the Notch pathway contributed to this effect. Targeting early hematopoiesis may be considered as a viable alternative in the existing arsenal of supportive therapies in sepsis.

Despite great efforts and numerous clinical trials, there is still a major need for effective therapies for sepsis. Neutralization or elimination of bacterial toxins remains a promising approach. The understanding of the interaction of the endotoxin (lipopolysaccharide, LPS) of Gram-negative bacteria with its cellular receptor, namely the CD14/TLR4/MD2 complex, was a major breakthrough. Unfortunately, clinical trials for sepsis on the neutralization of LPS or on the inhibition of TLR4 signaling failed whereas those on LPS removal remain controversial. Recent discoveries of another class of LPS receptors localized within the cytoplasm, namely caspase-11 in mice and caspases-4/5 in humans, have renewed interest in the field. These provide new potential targets for intervention in sepsis pathogenesis. Since cytoplasmic recognition of LPS induces non-canonical inflammasome pathway, a potentially harmful host response, it is conceivable to therapeutically target this mechanism. However, a great deal of care should be used in the translation of research on the non-canonical inflammasome inhibition due to multiple inter-species differences. In this review, we summarize the knowledge on endotoxin sensing in sepsis with special focus on the intracellular sensing. We also highlight the murine versus human differences and discuss potential therapeutic approaches addressing the newly discovered pathways.