"Apoptotic" Silica PartIcles to Resolve INflammation in inflammatory bowel disease – ASPIRIN

In the context of chronic inflammatory bowel disease (IBD), unachieved resolution has been proposed as an immunologic cause. While resolution terminates inflammatory response, leading to hemostasis and tissue healing, unachieved resolution nests chronic inflammation that then turns out pathological. One critical step in the resolution process is the removal of apoptotic cells (AC) by macrophages, generating anti-inflammatory and reparative mediators. In IBD pathogenesis, neutrophils apoptosis and their attraction to the lesion is described deficient, limiting the initiation of the resolution. Pro-resolutive strategies are emerging and modify our view considering inflammatory disease treatment, shifting from inhibiting and depleting approaches to targeting reactivation of physiological patterns such as the resolution process promoting tissue regeneration. Based on UMR 1098 research, such approaches, and notably local supplementation in pro-resolutive factors, have shown success in experimental IBD to restore resolution. The ASPIRIN project lies in mimicking AC supplementation to trigger resolution through the oral administration of “apoptotic” surrogates. AC is characterized by the exposure of phosphatidylserine (PS) at the external cell membrane layer acting as an “eat-me” signal. Silica particles (SiP) ranging from 0,3 to 2µm will be produced to expose serine on their surface either by grafting its residues through click chemistry, or by surface adsorption of a phospholipidic bilayer containing PS. If we demonstrate that PS is a better substitute than serine, PS will be encapsulated in SiP. Various parameters will be assessed to ensure that these surrogates are recognized by macrophages and trigger tissue regeneration, which will be validated through in vitro and in vivo inflammatory models. ASPIRIN project will allow a better comprehension of the roles of serine and PS in the efferocytic process and will propose an innovative proof of concept to treat IBD.