Role of Inflammasome in immunoSuppressive cells induction upon sEpsis: the project RISE – RISES

Sepsis, the leading cause of death in intensive care units, represents a major public health challenge and has been recognized as a global public health priority by the WHO. Its pathophysiology involves intricate mechanisms associating an exacerbated systemic inflammatory response and profound immunosuppressive mechanisms, primarily driven by the differentiation of immunosuppressive cell subpopulations. The mechanisms of immunosuppression following sepsis remain partly understood, despite their major and significant contribution to sepsis-related mortality. A better understanding of these mechanisms will help identify new therapeutic strategies for treating sepsis.
Inflammasomes are supramolecular complexes that act as sensors of cellular stress, controlling the secretion of inflammatory cytokines (IL-1ß and IL-18) and pyroptosis, a form of pro-inflammatory cell death. Inflammasome pathways are rapidly activated after sepsis and are associated with an increased risk of death. In patients with gain-of-function mutations in inflammasome-related genes and in cancer patients, excessive inflammasome activation contributes to the differentiation of immunosuppressive myeloid cells. In this project, we hypothesize that excessive inflammasome activation plays a central role in inducing not only myeloid (M-MDSC, PMN-MDSC) but also lymphoid immunosuppressive cells (regulatory T cells, regulatory plasma cells) during sepsis.
We will evaluate this hypothesis through a translational research program combining two complementary approaches. In a large cohort of septic patients, we will describe the kinetics of inflammasome activation and the emergence of immunosuppressive cell subpopulations over time and characterize the correlation between these two phenomena. Using a mathematical modeling approach, we will compute the association between these phenomena and the risk of death following sepsis, with the aim of identifying predictive factors for sepsis-related mortality that could serve as potential biological markers.
In parallel, using a murine model of sepsis that replicates the immune alterations observed in patients, we will identify the molecular and cellular mechanisms linking canonical and/or non-canonical inflammasome pathways to the emergence of immunosuppressive cells, in order to demonstrate a causal relationship between these two phenomena.
Our project investigates a novel pathophysiological mechanism underlying the development of immunosuppressive cells during sepsis, with the innovative hypothesis that a common mechanism drives the emergence of all suppressive cell subsets. This study will provide a strong rationale for developing new therapeutic strategies to break the harmful cycle between inflammation and immunosuppression, ultimately reducing sepsis-related mortality. Additionally, the findings will help define biological markers to identify patients most likely to benefit from these new treatments, aligning with a personalized medicine approach.