PRIN 2022 Scorrimento - Prot. 2022LF828E

Even with the use of the more recent targeted therapies, 40-50% of adults with rheumatoid arthritis (RA) and children with juvenile idiopathic arthritis (JIA) do not achieve disease remission and therefore accrue damage with relevant economic and social costs. There is an unmet need to find novel pathways regulating inflammatory response that can be therapeutically targeted, as well as to identify novel biomarkers to predict response to treatments. Joint inflammation has been associated with a marked increase in NGF production, but there is no clear evidence on which cell types and mechanisms are under the control of NGF or of its precursor proNGF, and if their receptor inhibition may alter the course of the inflammation. The goal of this project is to fill this void demonstrating the novel pathogenic role of proNGF/p75NTR axis in chronic arthritis and how its activation affects the functions of the cell types involved in joint inflammation. This study will elucidate the molecular pathways regulated by proNGF through its receptor p75NTR during inflammatory responses in in vivo and in vitro models. Our hypothesis, based on previous results and many preliminary data on RA and JIA patients and an arthritis animal model, is that the activation of proNGF/p75NTR axis enhances pro-inflammatory mediator production contributing to the chronicity of inflammation. The identification of the mechanisms that regulate receptor expression and proNGF/NGF relative concentration will help to prospect novel therapeutic approaches to chronic arthritis. We will investigate also if dysregulation of proNGF/p75NTR axis is a biomarker of disease severity and predictor of response to treatments in pediatric and adult chronic arthritis patients. Using single-cell genomic, epigenomic and proteomic profiling technologies, as well as a computational network medicine approach, gene regulatory networks and key molecular players will be identified in biopsies of chronic arthritis patients. Subsequently, the studies in vitro will define, in purified cell populations involved in arthritis pathogenesis, how the identified regulatory networks and epigenetic mechanisms involving microRNAs and alarmins are modified by activation of p75NTR/proNGF axis and by p75NTR inhibition, and whether they reinforce this axis. The effects of p75NTR inhibition on the inflammatory response will be then verified in vivo, in animal arthritis models, by analyzing inflammatory infiltrate, cytokine production and effector mechanisms leading to cartilage and bone degradation. Through an integrated in vitro, in vivo and in silico approach, this project will generate a comprehensive body of evidence providing the rationale for the use of p75NTR antagonists in the treatment of chronic arthritis in humans.

Working group:

• Stefano Alivernini - Responsabile scientifico UCSC

Partners:

• Consiglio Nazionale delle Ricerche