1. Introduction
Allergic diseases such as allergic rhinitis, asthma, food allergy, atopic dermatitis, allergic contact dermatitis, and anaphylaxis contribute to the rising cost of health care and cause a lower quality of life. Allergy is characterized by immune responses by antigen-specific type 2 helper T (Th2) cells that are involved in the development of antigen-specific immunoglobulin E (IgE) responses produced following class switching of B cells1. T cell receptors (TCRs) in naïve CD4+ T cells recognize antigens upon co-stimulation by CD28 when contacting antigen-presenting cells (APCs). Antigen presentation to naïve CD4+ T cells induces their differentiation into effector and memory T cells, and triggers clonal expansion. Activated T cells produce IL-2, which stimulates T cell proliferation, by autocrine or paracrine signaling2,3. Naïve CD4+ T cells can differentiate into at least four subtypes including Th1, Th2, Th17, and induced regulatory T (iTreg) cells4. Among these subsets of CD4+ T cells, Th2 cells are characterized by their production of interleukin (IL)-4, IL-5, and IL-13, and stimulate B cell class switching to produce antigen-specific IgE5.
Heme oxygenases (HO) are essential enzymes that catabolize heme into iron (Fe), biliverdin, and carbon monoxide (CO). Three isoforms of HO exist: the inducible form (HO-1) and constitutive forms (HO-2 and HO-3). In particular, HO-1 is an inducible enzyme expressed in mammalian tissues and plays a cytoprotective role6–8. It is well established that oxidative stress activates the nuclear factor erythroid 2-related factor 2 (NRF2) pathway resulting in HO-1 expression. In turn, HO-1 plays an essential role in maintaining intracellular homeostasis against excess reactive oxygen species (ROS) generated by redox signaling9, and protects cells against oxidative stress and inflammation10,11. In addition, HO-1 can regulate cell proliferation by arresting the cell-cycle by generating CO12,13. Previous studies investigating regulatory effects of HO-1 on T cells revealed that CO generated by HO-1 also suppresses CD4+ T cell proliferation by inhibiting IL-2 production14, and CO exposure suppresses proliferation and activation of T cells15,16. Phytochemicals obtained through fruit and vegetable consumption have protective effects against diverse diseases by inducing HO-1 expression by activating the NRF2 pathway17. Among these phytochemicals, quercetin, the aglycone of miqeulianin, has been reported to protect cells from oxidative stress and inflammation by generating HO-118,19, and recently, it was reported that quercetin suppresses T cell proliferation via HO-1 generation20.
In a previous study, we revealed that Rosae multiflorae fructus extract ameliorates OVA-induced allergic rhinitis symptoms in a mouse model, and identified miquelianin as the active compound of Rosae multifloraefructus21. Miqeulianin (quercetin 3-O -glucuronide, MQL), one of the flavonoids, is a quercetin glycoside. MQL has been reported to have antioxidant22, antidepressant23, and antiproliferative effects24. However, it is unknown if MQL affects allergic diseases or regulates Th2 immune responses. Thus, in this study, we examined the effect of MQL on a TMA-induced AD-like mouse model, and investigated the mechanisms by which MQL regulates Th2-related immune responses in vitro .