Systemic lupus erythematosus (SLE) is regarded as a systemic autoimmune disease (Kiriakidou and Ching, 2020). Patients suffered from SLE present a variety of symptoms such as, painful joints, fever, mouth ulcers and kidney injury, which seriously affect the health and life quality of patients (Askanase et al., 2012; D. Li et al., 2019). Splenomegaly is considered a manifestation of active SLE, although it may not frequently found in SLE patients (Colmegna et al., 2005; Zuckerman et al., 1993). Splenomegaly is resulted from elevated splenic function, congestion, or infiltration (Palmiere et al., 2019; Tsai et al., 2017; Yang et al., 2018). The role of spleen as a target organ of SLE cannot be ignored (Zhang et al., 2019). Moreover, SLE is characterized by aberrant activity of the immune system including several immunological defects (high concentration of autoantibodies in the serum and impaired regulatory T cell function) (Liu et al., 2017). The etiology of SLE remains unclear, and T helper (Th) cells (CD4+ cells) are considered to play a vital role in the induction and development of SLE.

Th17 cells, characterized by the expression of retinoid-related orphan receptor-gammat (RORγt) and the production of interleukin (IL)− 17, are a subset of CD4+ T cells (J. Y. Lee et al., 2020). Th17 cells are the continuation of the Th1 cells-initiated inflammatory process. Th17 cells have been reported to be involved in the pathogenesis of many autoimmune diseases including SLE, psoriatic arthritis, and rheumatoid arthritis (Jin et al., 2018; Nguyen et al., 2021; Wang et al., 2017). A small subset of Th17, known as Th17.1 cells, could not only produce IL-17, but also Th1 phenotype-like interferon-gamma (IFN-γ) (Patrick et al., 2022; Tsanaktsi et al., 2018). The nomenclature of Th17.1 is not uniform (Ramstein et al., 2016), and these cells have been referred to as Th1/17 (Duhen and Campbell, 2014), Th17/Th1 (Annunziato et al., 2007; Maggi et al., 2012), Th1.17 (Patrick et al., 2022), as well as Th17.1 cells to capture their transformed state (Ramesh et al., 2014). Accumulating evidences have proven that Th17.1 cells are expanded in patients with SLE (Tsanaktsi et al., 2018; Zhong et al., 2017). T cells from patients with SLE release higher levels of IFN-γ and IL-17 following stimulation (Tsanaktsi et al., 2018). Thus, targeting Th17 and Th17.1 cells is expected to be a strategy for the treatment of SLE. Moreover, the differentiation and activation of the Th17 and Th17.1 cells is regulated by the transcription factor RORγt (Annunziato et al., 2007; Nistala et al., 2010; Shibata et al., 2018), which acts as a vital part in the balance of regulatory T (Treg)/Th17 cells(Burgler et al., 2010; Shi et al., 2019). Autoimmunity is associated with a perturbed Treg compartment (Cruz et al., 2017). Thus, the potential of these T cells in the pathological process of SLE evokes us much attention.

SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) is an E3 ubiquitin ligase that catalyzes the ubiquitination of substrates for subsequent proteasomal degradation (Franco et al., 2017). It has been reported that SMURF1 involves in the regulation of immunity by controlling the ubiquitination and degradation of TRAF family proteins (S. Li et al., 2010). The anti-inflammatory function was at least partly mediated by the promotion of SMURF1 on MyD88 ubiquitination (Cao and Zhang, 2013; Y. S. Lee et al., 2011; Peng et al., 2022). These studies indicate the potential of SMURF1 in the regulation of inflammation and immunity. Moreover, the knockdown of SMURF1 upregulate the expression of IL-6 (X. Ma et al., 2019), and SMURF1 overexpression inhibiting the IFN-γ signaling (Yuan et al., 2012). Several factors including IL-6 relieve the repression of RORγt, thereby facilitating Th17 differentiation (Zhou et al., 2008). Therefore, we considered whether SMURF1 could play a role in the differentiation of Th17 and Th17.1 cells in the process of SLE. However, there have been no reports on it.

In the current study, we investigated the effects of SMURF1 on Th17 and Th17.1 differentiation in vitro, and further explored its role in the Treg/Th17 imbalance in SLE mice in vivo. Moreover, the underlying mechanism was subsequently elucidated. The study lays a foundation of the pathogenesis of SLE and provided a novel idea for the treatment of SLE.