Understanding the Cellular Origin of the Mononuclear Phagocyte System Sheds Light on the Myeloid Postulate of Immune Paralysis in Sepsis

Abstract

Sepsis, in essence, is a serious clinical condition that can subsequently result in death as a consequence of a systemic inflammatory response syndrome including febrile leukopenia, hypotension, and multiple organ failures. To date, such life-threatening organ dysfunction remains one of the leading causes of death in intensive care units, with an increasing incidence rate worldwide and particularly within the rapidly growing senior population. While most of the clinical trials are aimed at dampening the overwhelming immune response to infection that spreads through the bloodstream, based on several human immunological investigations, it is now widely accepted that susceptibility to nosocomial infections and long-term sepsis mortality involves an immunosuppressive phase that is characterized by a decrease in some subsets of dendritic cells (DCs). Only recently substantial advances have been made in terms of the origin of the mononuclear phagocyte system that is now likely to allow for a better understanding of how the paralysis of DCs leads to sepsis-related death. Indeed, the unifying view of each subset of DCs has already improved our understanding of the pivotal pathways that contribute to the shift in commitment of their progenitors that originate from the bone marrow. It is quite plausible that this anomaly in sepsis may occur at the single level of DC-committed precursors, and elucidating the immunological basis for such a derangement during the ontogeny of each subset of DCs is now of particular importance for restoring an adequate cell fate decision to their vulnerable progenitors. Last but not least, it provides a direct perspective on the development of sophisticated myelopoiesis-based strategies that are currently being considered for the treatment of immunosenescence within different tissue microenvironments, such as the kidney and the spleen.

Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia

“…In case of inflammation, an increase in the proportion of mo-DCs, which are more susceptible to polarization toward immunosuppressive functions by the local microenvironment, is also a cause of “sepsis induced immunosuppression.” Indeed, these mo-DCs have also been reported to induce TH2 and TH17 responses ( 59 , 60 ). Sepsis-induced immunologic dysregulation occurs at every level of the ontogeny of each subset of DCs ( 61 ). Considering these results, several teams have hypothesized that the correction of the number of DCs after inflammation, notably by injecting FLT3L which is the DC growth factor, can restore immune-competence and limit the susceptibility to secondary pneumonia ( 47 , 62 , 63 ).…”

“…TGF-β molecules act as cellular switches regulating numerous physiological processes such as immunity, cell renewal and healing. TGF-β is a pleiotropic cytokine involved in the development of Treg lymphocytes by inducing the Foxp3 transcription factor expression in CD25 − naive T cells in order to enforce the transition to Treg cells ( 61 ). TGF-β are expressed constitutively by a wide variety of cells in the lung, including myeloid cells (DCs and alveolar macrophages), T cells and fibroblasts ( 83 ).…”

A Comparison of Cs-137 γ Rays and 320-kV X-Rays in a Mouse Bone Marrow Transplantation Model

“…A systematic error of 1.35/0.76 (RBE estimates ratio) %1.8 would explain the result; however, such a large systematic error is unlikely, given that for killing bone marrow cells by X-rays the central estimate of the RBE is 1.35, which is quite close to the value of 1.3 used in the study design. 13 As murine hematopoiesis has been shown to take place not only in the bone marrow but also in the spleen, 23,24 splenocyte survival may be a significant contributing factor in the ability of the X-ray-irradiated mice to have repopulated their hematopoietic system with their own cells, rather than donor bone marrow. In addition, it is interesting to note that the lowest exposure level used for g rays (target dose 2.03 Gy) spared significantly more splenocytes than the other 2 higher g-ray exposures and the low g-ray exposure did not allow for allogeneic bone marrow engraftment.…”

Sepsis target validation for repurposing and combining complement and immune checkpoint inhibition therapeutics

“…The PD-1/PD-L1 axis is the most well studied immune checkpoint interaction in sepsis immunopathology and has been shown to be involved in intestinal and liver injury during sepsis. However, additional studies are required to reveal the exact role of PD-L1 in various organ injuries such as kidney, brain, lung, heart and others during sepsis 23,82,[116][117][118][119][120] .…”