Il-6 signaling exacerbates hallmarks of chronic tendon disease by stimulating reparative fibroblasts

Abstract

Tendinopathies are debilitating diseases currently increasing in prevalence and associated costs. There is a need to deepen our understanding of the underlying cell signaling pathways to unlock effective treatments. In this work, we screen cell signaling pathways in human tendinopathies and find enriched IL-6/JAK/STAT signaling alongside signatures of cell populations typically activated by IL-6 in other tissues. To dissect the underlying causalities, we combine IL-6 knock-out mice with an explant-based assembloid model of tendon damage to successfully connect IL-6 signaling to fibroblast progenitor activation and recruitment. Vice versa, we show that these fibroblast progenitors promote the development of tendinopathy hallmarks in the damaged explant upon IL-6 activation. Finally, we present in vivo data confirming diminished migration of progenitors to acute Achilles tendon lesions in IL-6 knock-out mice. We conclude that IL-6 activates tendon tissues to initiate normal healing processes that can deteriorate into tendinopathy hallmarks.