Innate Lympoid Cells Typ 3 (ILC3) induce a profibrotic phenotype in macrophages to promote fibrotic tissue remodeling in systemic sclerosis (SSc)

• Applicant: Professor Dr. Jörg Hans Wilhelm Distler
• Subject Area: Rheumatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 554988076

Fibrosis describes the excessive deposition of extracellular matrix in tissues in response to a trigger or injury. The accumulation of extracellular matrix (ECM) proteins perturbs the normal architecture and may impair organ function and fibrotic tissue responses may contribute to 45% of all deaths in the industrialized world. SSc is a prototypical systemic fibrotic disease that affects the skin and various internal organs. In SSc as in other fibrotic diseases, myofibroblast as key effector cells of fibrosis reside predominantly in close proximity to inflammatory cells in SSc. Amongst the different leukocyte subsets, alternatively activated macrophages (AAM) are thought to play a particularly important role in fibroblast activation. AAM are a rich source of multiple profibrotic cytokines. However, the cellular interactions and molecular mechanisms that induce alternative activation of macrophages in fibrotic diseases remain incompletely understood. We propose type 3 innate lymphoid cells (ILC3) as novel profibrotic cellular players in SSc. Our preliminary results demonstrate that ILC3 are increased in SSc and that the adoptive transfer of ILC3 into Rag2/IL2Rg deficient mice exacerbates fibrosis. RNASeq of tissues from those mice reveals a strong signature of alternatively activated macrophages and ILC3 foster alternative activation of macrophages, whereas ILC3 did not activate fibroblasts directly in coculture experiments. With the current proposal, we aim to further validate ILC3 as novel cellular players in fibrotic diseases and to characterize the molecular pathways, by which they induce profibrotic polarization of macrophages and drive tissue fibrosis. The applicant is aiming to identify ILC3-induced profibrotic macrophage populations using scRNASeq, to validate and functional characterize ILC3-induced profibrotic macrophages and to translate the findings from mouse models to human SSc.

• DFG Programme: Research Grants