Translational Medicine - Posters P
1 Nantes Université, Inserm, Center for Research in Transplantation and Translational Immunology,
UMR1064, Nantes, France
2 Surgical intensive care unit,CHU Nantes, Franc
Patients hospitalized with sepsis or trauma have a higher risk of developing hospital-acquired pneumonia (HAP) due to an immune suppressive effect of the condition that led to hospitalization. To date, the only available treatments for HAP are antibiotics, which aim to prevent lung contamination and maintain sterile airways, but the attributable mortality remains higher than 10%. We are now developing a new concept that has the potential to overcome the classical theory of pneumonia genesis and revolutionize the prevention and treatment of this condition.
Alveolar macrophages (R-MAC) provide the first line of defense against respiratory pathogens. After the resolution of inflammation, we reported on a long-lasting inability of R-MAC to effectively phagocytose bacteria. We showed that R-MAC underwent an epigenetic program of tolerogenic training that led to their ‘immunoparalysis’. We found that the changes in the microenvironment observed during pneumonia are in part mediated by the stimulation of the Sirpa receptor, resulting in the reduced phagocytic capacity of the R-MAC.
We hypothesize that Sirpa signaling early after the primary inflammation triggers an immune-suppressive lung environment, leading to functional impairment of R-MAC.
We are now investigating (1) the chemical blockade of Sirpa by targeting both allosteric and catalytic sites of SHP2 (downstream molecule of the Sirpa pathway) aiming to restore the phagocytic capacity of R-MACs and (2) the signaling pathway by which Sirpa modifies the microenvironment.
We are associating
1. in silico transcriptomic analysis (scRNAseq, RNAseq and ATAC-seq),
2. in vivo analysis on our model of Sirpa knockout mouse (Sirpa-/-) by flow cytometry,
3. and in vitro culture of bone-marrow derived macrophages (BMDMs) from Sirpa+/+ and Sirpa-/- mice
to be able to identify Sirpa-dependent functions that induce an immunosuppressive lung environment in patients.
The in vitro model of Sirpa stimulation on BMDMs by the surfactant protein D is allowing to investigate the signaling pathway of Sirpa. Transcriptomic analysis revealed the agonists of the microenvironment interacting with Sirpa in the time of inflammation. Plus, preliminary results with chemistry-driven optimization of SHP2 inhibitors is increasing the phagocytic capacity of murine macrophages, suggesting a promising strategy for human patients with pneumonia.