Innate Lymphoid Cells induce a fibrotic phenotype of fibroblasts in fibrotic diseases

• Applicant: Professor Dr. Andreas Ramming
• Subject Area: Immunology ; Rheumatology
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320379231

Fibrotic diseases impose a major socioeconomic burden on modern societies and account for up to 45% of deaths in the developed world. Despite the great medical need, anti-fibrotic therapies are not yet available for clinical use. Fibrotic diseases can affect virtually every organ system. They can be restricted to single organs, as in idiopathic pulmonary fibrosis (IPF), or may affect multiple organs, as in systemic sclerosis (SSc). SSc is a prototypic multisystem fibrotic disorder that disrupts the physiological architecture of affected tissue by an excessive accumulation of extracellular matrix. The current concept of the pathogenesis of multisystem fibrotic diseases postulates a triad of inflammation attributed to humoral and cellular immune abnormalities, vasculopathy and fibrosis. However, the mechanisms in this fundamentally important process of tissue injury are incompletely understood. Fibrotic diseases and normal wound healing share a common tissue repair response in the initial stages. This common repair response is characterized by an inflammatory reaction with leukocyte infiltration into the affected tissues. The release of pro-inflammatory and pro-fibrotic mediators from these infiltrating leukocytes activates fibroblasts and stimulates the release of collagen and other components of the extracellular matrix. Fibrotic diseases fail to efficiently terminate this repair program. In normal wound healing, inflammation and fibroblast activation are limited to the site of injury and are turned-off right after appropriate repair. A growing body of evidence suggests that overproduction of extracellular matrix components results from complex interactions between various cells, including leukocytes and fibroblasts. More recently, locally accumulating innate-like lymphoid cells (ILCs) are emerging as an important cellular source of cytokines triggering fibrotic tissue remodeling independently of the adaptive immune system. Therefore, we aim to further characterize ILCs and to validate ILC2s as therapeutic target in fibrotic diseases.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells