Systemic erythematosus lupus (SLE) is a chronic autoimmune disease in which the immune system attacks healthy cells and tissues, resulting in the deposition of immune complexes that cause damage to multiple organs, such as the skin and mucous membranes and the musculoskeletal, haematologic, and renal systems [1,2]. The pathogenesis of SLE is complex and may be related to genetic, environmental, and immune disorders [3].

T cells play an important role in the pathogenesis of SLE by secreting proinflammatory cytokines such as IFNγ, TNF-α, and IL-6 and affecting other immune cells to amplify inflammatory responses [4,5]. Among various T-cell subpopulations, a minor group of T lymphocytes in healthy physiology express neither CD4 nor CD8 but do express αβ or γδ T-cell receptors. These T lymphocytes are termed double-negative T (DNT) cells. Interestingly, DNT cells are increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients, especially during the active phase of their disease. Accumulated DNT cell infiltration is further detected in the kidneys of SLE patients and is associated with reduced renal function (in terms of blood uremic nitrogen levels) and a more active state of DNT cells expressing Ki67 [[6], [7], [8], [9], [10], [11]]. In addition, DNT cells not only secrete a variety of cytokines, including IL-4, IL-17, IFNγ, and TNF-α [12,13] but also promote antibody production by B cells to further aggravate tissue damage in experimental lupus mouse models [13,14]. Notably, two recent studies reported that the neddylation pathway orchestrates the homeostasis of DNT cells, thereby participating in the pathogenesis of lupus [15,16]. Therefore, DNT cell homeostasis plays an important role in the progression of lupus, and drugs that target DNT cell homeostasis are assumed to alleviate lupus symptoms.

Currently, glucocorticoids, immunosuppressants and targeted biologics are used to treat SLE in clinical practice [1,2,17]. However, the administration of corticosteroids such as prednisone and methylprednisolone, as well as immunosuppressants such as cyclophosphamide and mycophenolate mofetil, often causes a series of adverse effects, such as osteoporosis, gastrointestinal complications and gonadal suppression [18]. Some targeted biologics, such as belimumab, have the disadvantages of inconvenient intravenous administration, high cost and a low clinical response rate [19,20]. Therefore, it is necessary to find drugs that can effectively improve SLE with fewer side effects.

Curcumin is a natural polyphenol product with a wide range of pharmacological effects and has been shown to have immunomodulatory and anti-inflammatory effects in a variety of diseases [[21], [22], [23]]. Curcumin can exert immunomodulatory effects by interacting with immune cells (T cells, B lymphocytes, macrophages, neutrophils, etc.), cytokines and various transcription factors, such as nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and signal transducer and activator of transcription (STAT) [23]. Curcumin has been shown to attenuate lupus nephritis in lupus-like model mice by suppressing macrophage-secreted B-cell activating factor (BAFF) [24], inhibiting the NLRP3 inflammasome [25], and modulating neutrophils [26]. However, how curcumin regulates DNT cells to result in the remission of SLE is unclear.

In this study, we evaluated the efficacy of curcumin in the treatment of SLE in different mouse models and further explored the underlying mechanism by which curcumin improves the profiles of SLE by suppressing the proportion and activation status of DNT cells. Our work provides a new target and strategy for the treatment of SLE with curcumin.