We have identified CSF-1 and Th17/Tc17 derived IL-17 as key cytokines that promote sequestration and differentiaton of fibrogenic tissue macrophages, and the critical role of Ly6Clo monocyte derived macrophages, in driving cGVHD pathology. Although each represents a targetable entity, IL-17, CSF-1, TGFb and macrophages themselves all play important roles in homeostatic processes including mucosal immunity and microbiome diversity (IL-17), tissue remodelling (CSF-1, TGFb) and tolerance (TGFb). Thus, the ablation of any one of these modalities will likely have associated deleterious consequences. We therefore propose to elucidate how IL-17 signalling in monocytes/macrophages promotes fibrogenic macrophage differentiation after SCT to identify new targetable fibrogenic pathways and molecules evoked in these cells after SCT. This will allow the development of alternative therapeutic strategies to preferentially attenuate fibrogenic responses whilst sparing protective homeostatic pathways.
- IL-17 promotes pathogenic profibrotic donor macrophage differentiation after SCT.
- Pathogenic macrophages utilise differentiation programs that will serve as tractable therapeutic targets for the treatment of cGVHD.
These studies utilise our established preclinical models of skin and lung GVHD to elucidate the direct and relative contribution of IL-17 to the migration, activation, and/or differentiation of profibrogenic monocytes/macrophages within target organs.