Inflammatory and Fibrotic Responses to Malondialdehyde-Acetaldehyde Adducts in Rheumatoid Arthritis

Omaha Va Medical Center, Omaha NE

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Abstract

With an aging population and epidemiologic risk factors that include cigarette smoking and military burn pit exposures, the burden posed by rheumatoid arthritis (RA) and fibrotic RA-associated interstitial lung disease (RA-ILD) will grow dramatically among U.S. veterans in coming years. Despite the availability of advanced therapies, up to half of RA patients do not achieve adequate disease control, contributing to increased morbidity and mortality. No current therapies in RA simultaneously target the inflammation and fibrosis that characterize RA or RA-ILD. A long-term goal of our research team is to identify novel treatment targets in RA by defining the pathogenic role that post-translationally modified proteins (PTMs; citrulline [CIT] or malondialdehyde- acetaldehyde [MAA]) play in RA pathogenesis. Previously, our group demonstrated that MAA-modified proteins are abundant in RA synovium and in lung tissues where they strongly co-localize with CIT. We have generated robust preliminary data demonstrating that dually-modified proteins (CIT+MAA) result in macrophage (MΦ) activation that uniquely yields both pro-inflammatory and pro-fibrotic effects. CIT+MAA-induced activation leads to increased expression and function of calcium (Ca++) dependent peptidyl-arginine deiminase (PAD), furthering protein citrullination, and producing soluble mediators that crosstalk with human fibroblasts to produce extracellular matrix (ECM). Therefore, our overarching hypothesis is that co-modified protein leads to a mixed M1-like (pro-inflammatory) and M2-like (pro-fibrotic) MΦ phenotype that promotes tissue inflammation and fibrosis via the production of both citrullinated and non-citrullinated mediators. To investigate this hypothesis, studies in Aim 1 will identify mechanisms by which MAA-modified and/or CIT proteins activate human MΦs leading to increased PAD expression and function. In Aim 2, we will identify soluble mediators secreted by MΦs in response to stimulation with CIT±MAA-modified proteins that promote fibroblast function and ECM deposition. This will include translational studies to examine the relationship of a soluble mediator already identified in preliminary work (platelet-derived growth factor [PDGF]-BB) with the development of incident RA-ILD using a uniquely available longitudinal cohort of U.S. veterans with RA. In Aim 3, we will leverage a novel murine model of RA-ILD that combines collagen-induced arthritis (CIA) and lung injury to quantify the anti-inflammatory and anti-fibrotic efficacy of targeted inhibitors of CIT/MAA formation and PDGF- BB signaling. At the completion of this research, we anticipate having a precise understanding of how CIT and MAA-modified proteins together (and in isolation) facilitate RA and RA-ILD progression through MΦ activation, MΦ-fibroblast crosstalk, inflammation and fibrosis. Results will include the identification of targetable pathways that will ultimately open new avenues of translational research and yield novel therapeutic approaches in RA.