Role of CX3CR1 expression on Monocytes during sepsis – a translational study – CMOS

Sepsis is defined as a widespread inflammation secondary to an infection. It will strike more people every year than lung, breast and prostate cancers combined and its incidence is raising. Sepsis is a dual disease, inflammation is predominant in the early phase and leads to organ failures, while in the latter phase of the disease, patients present features of immunoparalysis and are likely to die from nosocomial infections. Current treatment of sepsis focuses on the consequences rather than the cause of sepsis and is based on antibiotherapy, fluid expansion and replacement therapy for organ failures; inflammation is not treated. The development of new treatments and a better understanding of this syndrome are essential.
The main effectors of inflammation are the myeloid leukocytes, especially the monocytes / macrophages (Mo/Mac). Systemic inflammation is associated with a production of chemokines (chemotactic cytokines) and signaling/adhesive molecules that will lead to tissue infiltration by myeloid cells during the early phase of sepsis. Mo that are responsible for the inflammatory activation are also involved in the resolution of this inflammation and immunosuppression. Mo infiltration is controlled by several factors, especially two chemokines: CCL2 (MCP-1) and CX3CL1 and their cognate receptors, CCR2 and CX3CR1.
The objectives of our project are to decipher the mechanisms leading to the activation of the (innate) immune response and its shift toward an immunoanergic profile. Its program aims specifically to a better understanding of the role of the chemokine receptor CX3CR1 expression on Mo, Mac, dendritic cells (DC) and so-called Myeloid Derived Suppressor Cells (MDSC) in space and time, i.e. in different compartments (bone marrow, blood, organs) and at different time point during sepsis. CX3CR1 is mainly expressed by Mo/Mac/ DC and few recent studies, including ours, point out the critical role of this chemokine receptor during sepsis. At the early phase, CX3CR1 mediates Mo protective functions and Mo/Mac/DC activation and survival. At the latter phase, CX3CR1 may be involved in the generation of MDSCs and tissues replenishment by circulation Mos/MDSC, thus contributing to the immunosuppressive state.
Our aims are:
1. To determine the precise roles played by CX3CR1 in the initial phase of sepsis: we will perform comprehensive studies on monocyte (and other leukocytes) recruitment, survival and differentiation/functions of Mac/DC and impact of CX3CR1 modulation on tissue damage and survival.
2. To characterize the role of CX3CR1 in the constitution of sepsis-induced immunosuppression (IS): we will analyze Mo/Mac/DC survival, functions (phagocytosis and antigen presentation), tissue Mac-DC replenishment, generation of myeloid-derived suppressor cells (MDSCs) and impact of CX3CR1 modulation on response to a 2nd infectious hit.
3. To determine what signaling pathways are elicited by CX3CR1 activation in both inflammatory phase and IS and identify therapeutic targets.
Our research program is organized in 4 tasks, the first one is the coordination of the project, the 2nd task will characterize the “phenotype” of CX3CR1 modulation during early and/or late phase of sepsis, the 3rd task will analyze transcriptome/cytokinome/proteome alteration along sepsis and the 4th task will identify signaling pathways triggered along sepsis. Our study is designed in a translational study with a unique trio of models: murine models of sepsis, volunteer receiving low-dose LPS (enrolled in an independent approved and granted clinical trial) and septic patients.
This program could lead to a better understanding of the pathogenesis of sepsis and the identification of novel targets to treat septic patients. We will characterize the response of Mo/Mac/DCs to CX3CR1 modulation and pave the way to possible future clinical trial in proof of concept, small sized study that will be followed, if successful, by large scale randomized controlled trials.