Background/Purpose: Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology that is characterized by vasculopathy, fibrosis, and inflammation. Our work and that of others have implicated MØs in SSc pathogenesis and thus targeting MØs may have significant therapeutic benefit. We have shown that MØs are aberrantly activated in SSc, releasing inflammatory mediators and inducing activation of fibroblasts. We now show that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) inhibits immune activation and oxidative stress in SSc MØs, resulting in inhibited expression of TGF-b, CCL2, and IL-6 and enhanced activation of Nrf2 signaling.

Methods: Plasma and PBMCs were obtained from whole blood of 7 SSc patients or 5 healthy age and gender-matched control subjects following informed written consent. CD14⁺monocytes were isolated from PBMCs using magnetic bead selection, and were cultured with either autologous or allogeneic plasma for 7 days to differentiate the cells into MØs. Immune activation studies were performed using 10 ng/ml LPS. RNA expression in MØs was analyzed using qRT-PCR, and protein expression and secretion were monitored using flow cytometry and by ELISA.

Results: CDDO-Me markedly inhibits basal mRNA and protein expression of TGF-b, CCL2, and IL-6 in SSc MØs, and attenuates surface expression of CD163 and CD206, which are upregulated on pro-fibrotic SSc MØs. We further demonstrate that CDDO-Me upregulates targets of Nrf2 activation in SSc MØs, suggesting CDDO-Me attenuates oxidative stress in these cells. CDDO-Me treatment does not impair SSc MØviability.

Conclusion: Our data suggest that CDDO-Me attenuates inflammatory activation and induces anti-oxidant activity in SSc MØs. For the first time, we have shown that CDDO-Me treatment attenuates the pro-fibrotic activation profile of SSc MØs. For the first time, we have also shown that CDDO-Me inhibits expression of surface markers and cytokines associated with SSc inflammation and pathogenesis. In addition to regulating these factors, CDDO-Me also induces Nrf2 activation in SSc MØs. As CDDO-Me is currently undergoing Phase III clinical trial testing in patients with pulmonary arterial hypertension, a frequent complication and leading cause of death in SSc, potential repositioning of this drug to treat SSc is especially exciting. Because there are still no FDA-approved disease-modifying therapies that target innate immune activation in SSc, CDDO-Me may be a potentially important drug in our arsenal of therapeutics to combat MØ activation in this disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-inflammation-and-oxidative-stress-in-systemic-sclerosis-ssc-macrophages/