Abstract
Biochanin A (BCA) is a natural organic compound of the class of phytochemicals known as flavonoids and isoflavone subclass predominantly found in red clover (Trifolium pratense). It has anti-inflammatory activity and some pro-resolving actions, such as neutrophil apoptosis. However, the effect of BCA in the resolution of inflammation is still poorly understood. In this study, we investigated the effects of BCA on the neutrophilic inflammatory response and its resolution in a model of antigen-induced arthritis. Male wild-type BALB/c mice were treated with BCA at the peak of the inflammatory process (12 h). BCA decreased the accumulation of migrated neutrophils, and this effect was associated with reduction of myeloperoxidase activity, IL-1β and CXCL1 levels, and the histological score in periarticular tissues. Joint dysfunction, as seen by mechanical hypernociception, was improved by treatment with BCA. The resolution interval (Ri) was also quantified, defining profiles of acute inflammatory parameters that include the amplitude and duration of the inflammatory response monitored by the neutrophil infiltration. BCA treatment shortened Ri from ∼23 h observed in vehicle-treated mice to ∼5.5 h, associated with an increase in apoptotic events and efferocytosis, both key steps for the resolution of inflammation. These effects of BCA were prevented by H89, an inhibitor of protein kinase A (PKA) and G15, a selective G protein–coupled receptor 30 (GPR30) antagonist. In line with the in vivo data, BCA also increased the efferocytic ability of murine bone marrow–derived macrophages. Collectively, these data indicate for the first time that BCA resolves neutrophilic inflammation acting in key steps of the resolution of inflammation, requiring activation of GPR30 and via stimulation of cAMP-dependent signaling.
Highlights
Arthritis is a severe inflammatory disease characterized by synovial inflammation, production of inflammatory mediators, intense pain, destruction of cartilage and bone, and systemic dysfunctions (Firestein, 2003; McInnes and Schett, 2017; Smolen et al, 2018)
Using a well-characterized model of antigen-induced arthritis (AIA), we demonstrate that therapeutic administration of Biochanin A (BCA) resolves neutrophilic inflammation acting in key steps of the resolution of inflammation, requiring activation of G protein–coupled receptor 30 (GPR30), and via stimulation of cyclic adenosine monophosphate (cAMP)-dependent signaling
To study the effect of BCA on the inflammatory response and resolution, we used a well-established model of AIA characterized by an intense influx of leukocytes, predominantly neutrophils, which peaked from 12 to 24 h after the challenge with mBSA (Lopes et al, 2011)
Summary
Arthritis is a severe inflammatory disease characterized by synovial inflammation, production of inflammatory mediators, intense pain, destruction of cartilage and bone, and systemic dysfunctions (Firestein, 2003; McInnes and Schett, 2017; Smolen et al, 2018). The resolution of inflammation is a complex process and actively orchestrated by specialized pro-resolving mediators that collaborate efficiently to inhibit the influx of leukocytes to the inflamed site, shutting down molecules of intracellular pathways associated with cytokine production and leukocyte survival (especially neutrophils) (Serhan and Savill, 2005; Alessandri et al, 2013; Fullerton and Gilroy, 2016; Feehan and Gilroy, 2019), which eventually will lead to apoptosis of these cells and their subsequent removal by macrophages in a process named efferocytosis (Poon et al, 2014; Green et al, 2016; Morioka et al, 2019; Lawrence et al, 2020) These steps lead to the resolution of inflammation and tissue repair and represent the potential therapeutic target for resolution pharmacology (Martin et al, 2015; Perretti et al, 2015; Greenlee-Wacker, 2016; Sugimoto et al, 2016). A failed neutrophil apoptosis and an impaired efferocytosis are correlated with the severity of the disease (Abdolmaleki et al, 2018)
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