Cordyceps proteins alleviate lupus nephritis through modulation of the STAT3/mTOR/NF-кB signaling pathway

Systemic lupus erythematosus (SLE) is a representative systemic autoimmune disease, leading to multiple organs damage (Almaani et al., 2017; Kiriakidou and Ching, 2020). Lupus nephritis (LN) is a common complication of SLE and a major risk factor for morbidity and mortality (Kiriakidou and Ching, 2020). Particularly, it affects the kidneys in about 50% of patients (Tsokos, 2011). Both genetic and environmental factors are thought may be involved in LN (Rahbar et al., 2019). Furthermore, LN patients may have an elevated mTOR activity in CD4+ T cells and imbalance of T-helper 1 (Th1) and T-helper 2 (Th2) (Tilstra et al., 2018; Lech and Anders, 2013; Kong et al., 2003; Fernandez et al., 2009)., Both ex vivo and after in vitro activation, CD4+ T cells from the LN model exhibit elevated mitochondrial oxidative metabolism compared to non-autoimmune controls (Yin et al., 2015).

Treatment strategies for patients with LN vary according to the histological type of disease (Dall'Era, 2017). There are common drugs in clinic application, including cyclophosphamide, mycophenolate mofetil (MMF), azathioprine, glucocorticoids, and tacrolimus (Tunnicliffe et al., 2018). Corticosteroids were current widely used treatment, and immunosuppressants may be necessary in the later stages of LN (Almaani et al., 2017; Parikh et al., 2020). Although most of these traditional drugs are effective in reducing proteinuria of lupus mice (Atkins et al., 2005; Maschio et al., 1996), the adverse effects of these drugs should not be ignored. As an immunosuppressant, PA can be used in the treatment of clinical nephritis (Dai and Liu, 2018).

Cordyceps, generally known as the Chinese caterpillar fungus (or Dong chong xia cao in Chinese), is a unique and expensive medicinal complex of fungus Cordyceps (Berk.) Sacc. As a tonic, Cordyceps has been in use for hundreds of years as a traditional Chinese medicine (Zhu et al., 1998; Zhang et al., 2011). Its potential bioactive ingredients, polysaccharides, adenosine, cordycepin, cordycepic acid, and ergosterol (Wang et al., 2015; Liu et al., 2015), showed the immunomodulatory, anti-cancer, -inflammatory, -diabetic, and anti-oxidant effects (Wu et al., 2010; Zou et al., 2015). In the medical field, Cordyceps has been widely used as an immunoregulant after kidney transplantation (Ding et al., 2009). Several studies have already shown that Cordyceps can be used as an adjuvant to reduce graft lesions, prolong graft survival time, and the dose of cyclosporine (JordanHirsch et al., 2008). Besides, an inflammation experiment in vitro, they found that the inhibition of inflammation by Cordyceps may be related to the modulation of T helper (Th1) and Th2 cells functions (Chiou and Lin, 2012). However, the proteins of Cordyceps are rarely investigated, and the pharmacological activities of CP deserve further exploRation. Therefore, we treated MRL/lpr mice with CP to examine their impact on renal inflammation, apoptosis and fibrosis at the onset stage by immunohistochemistry and immunofluorescence, and further studied the therapeutic mechanism.

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