DAMP-Promoted Efferent Innate Immune Responses in Human Diseases: Fibrosis

Abstract

In Chapter 6, a selected clinically oriented update of the topic of controlled and dysregulated fibrotic processes is presented, as already briefly outlined in Vol. 1 of the book Damage-Associated Molecular Patterns in Human Diseases: Injury-Induced Innate Immune Responses. After a concise overview of the role of the extracellular matrix (ECM) in homeostasis, its contribution to pathological fibrogenesis is outlined. Thus, prolonged or severe tissue injuries can lead to excessive ECM production that results in an altered mechanical environment associated with increased ECM stiffness that, via mechanotransductive pathways, is considered a powerful driver of progressive fibrosis. The molecular mechanisms of mechanotransduction are described by focusing on various mechanosensors that mediate interaction between the ECM and cells such as fibroblasts (i.e., mechanisms of “inside-out and outside-in” signaling). In this context, evidence is discussed suggesting an interplay between DAMP-triggered pathways on the one side and mechanotransduction-mediated positive feed-forward loops, on the other hand. Particular focus is directed to the transforming growth factor-beta (denoted as an inducible DAMP) that triggers pathways in conjunction with mechanotransducing pathways. These processes are suggested to constitute self-perpetuating loops that potently propagate activation of myofibroblasts as the key cells in mediating fibrosis in a broad range of pathologies. The chapter is finished with a brief overview of epigenetic mechanisms reported to be involved in fibrosis.