Infiltrative monocytes modulated by adenosine deaminase 2 promote tissue inflammation and fibrosis in Crohn's disease

• Applicant: Dr. Shilpa Tiwari-Heckler
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553803409

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, which is associated with dysregulated innate and adaptive immune responses. Lack of primary therapeutic response and the refractory nature of this disease remain major challenges. Emerging evidence suggests that aberrant purinergic pathways, involving extracellular ATP- and adenosine mediated signals, contributes to tissue damage in CD. Our preliminary data suggests an unknown role of the novel enzyme adenosine deaminase 2 (ADA2) in modulating tissue inflammation in patients with CD. ADA2 is produced by activated monocytes/macrophages and converts extracellular adenosine into inosine. This proposal will investigate the functional role of ADA2 in shaping macrophage plasticity in the gut and orchestrating the interaction with pathogenetic Th17 cells. Our specific aims will test the following hypothesis: ADA2 expression by macrophages drives Th17 responses to exacerbate tissue damage in patients with CD. Aim 1: Tissue hypoxia and bacterial translocation due to epithelial barrier defects induce activation of monocytes/macrophages resulting in ADA2 release, which promotes tissue inflammation and fibrosis. Aim 2: ADA2 derived from intestinal macrophages drives Th17 responses to promote tissue inflammation and fibrosis. Aim 3: Targeting ADA2-dependent signaling in monocytes/macrophages by nanoparticle-encapsulated siRNA targeted therapy attenuates tissue inflammation in the combined humanized mouse model of experimental colitis.

• DFG Programme: Research Grants