Study summary · research use only
Elamipretide(SS-31) Attenuates Idiopathic Pulmonary Fibrosis by Inhibiting the Nrf2-Dependent NLRP3 Inflammasome in Macrophages
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This mouse study examined whether the mitochondrion-targeted peptide elamipretide (SS-31) affects idiopathic pulmonary fibrosis (IPF), using a bleomycin (BLM)-induced mouse model with SS-31 injected every other day. The abstract reports that SS-31 treatment suppressed BLM-induced pulmonary fibrosis and inflammation, with improved histological findings and decreased extracellular matrix deposition and inflammatory cytokine release; expression of IL-1β and IL-18 was reduced to less than half with SS-31 treatment. The authors describe SS-31 as inhibiting IL-33- or LPS/IL-4-induced production of IL-1β and IL-18 in macrophages by suppressing NLRP3 inflammasome activation, and report that Nrf2 was upregulated alongside improved mitochondrial function after SS-31 treatment, with no significant change observed in Nrf2-knockout mice and macrophages.
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disease with a limited therapeutic strategy. Mitochondrial oxidative stress in macrophages is directly linked to IPF. Elamipretide(SS-31) is a mitochondrion-targeted peptide that has been shown to be safe and beneficial for multiple diseases. However, whether SS-31 alleviates IPF is unclear. In the present study, we used a bleomycin (BLM)-induced mouse model followed by SS-31 injection every other day to investigate its role in IPF and explore the possible mechanism. Our results showed that SS-31 treatment significantly suppressed BLM-induced pulmonary fibrosis and inflammation, with improved histological change, and decreased extracellular matrix deposition and inflammatory cytokines release. Impressively, the expression percentage of IL-1β and IL-18 was downregulated to lower than half with SS-31 treatment. Mechanistically, SS-31 inhibited IL-33- or lipopolysaccharide(LPS)/IL-4-induced production of IL-1β and IL-18 in macrophages by suppressing NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome activation. Nuclear factor erythroid 2-related factor 2(Nrf2) was dramatically upregulated along with improved mitochondrial function after SS-31 treatment in activated macrophages and BLM-induced mice. Conversely, there was no significant change after SS-31 treatment in Nrf2-/- mice and macrophages. These findings indicated that SS-31 protected against pulmonary fibrosis and inflammation by inhibiting the Nrf2-mediated NLRP3 inflammasome in macrophages. Our data provide initial evidence for the therapeutic efficacy of SS-31 in IPF.
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