Abstract
IntroductionLupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristane-induced LN in mice.MethodsThe renoprotective effect of baicalein was detected in a pristane-induced lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed.ResultsBaicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome.ConclusionThe data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.
Highlights
Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE)
The data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of myeloid-derived suppressor cells (MDSCs) expansion and regulation of the balance of the Nuclear factor E2-related factor 2 (Nrf2)/HO-1 signal and NLRP3 expression in MDSCs
We observed that baicalein blocked the protein expression levels of NLRP3 inflammasome and phosphorylated Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 increased by the combination of LPS and Adenosine triphosphate (ATP) or by just LPS stimulation in MDSCs (Fig. 5h, i). These findings suggested that baicalein might protect against LN through the suppression of oxidative stress and inflammation in MDSCs, which associated with the inhibition of NLRP3/NF-κB activation and promotion of the expression of the Nrf2 signal
Summary
Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). The effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristaneinduced LN in mice. Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease, characterized by chronic inflammation and immunological abnormalities. While other studies suggested that MDSCs were pro-inflammatory and could promote the disease progress in chronic inflammation conditions, Wu H et al reported that the increased MDSCs in peripheral blood of patients are positively correlated with SLE and MDSCs promoted Th17 polarization by secreting Arg-1 in vitro [10]. We have found that MDSCs promoted Th17 polarization and inhibited Treg differentiation by IL-1β secretion to promote MRL/lpr lupus mice progress [11]. The involvement of MDSCs in LN progression is unclear
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