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Cell Stress Chaperones. 2012 Mar; 17(2): 267–274.
Published online 2011 Nov 1. doi: 10.1007/s12192-011-0305-3
PMCID: PMC3273564
PMID: 22042611
Prevention and treatment of alopecia areata with quercetin in the C3H/HeJ mouse model
Tongyu Cao Wikramanayake, Alexandra C. Villasante, Lucia M. Mauro, Carmen I. Perez, Lawrence A. Schachner, and Joaquin J. Jimenez

Abstract
Alopecia areata (AA) is an autoimmune non-scarring hair loss disorder. AA can be acute, recurrent, or chronic. Current therapeutic options for AA are limited, and there is no effective prevention for recurrent AA.

We have previously shown a correlation between the expression of HSP70 (HSPA1A/B), a heat shock protein involved in the inflammatory response, and the onset of AA in the C3H/HeJ mouse model. In this study, we tested the effects of quercetin, a bioflavonoid with anti-inflammatory properties, on AA development and HSP70 expression in the C3H/HeJ model.

Mice with spontaneous AA were treated with subcutaneous quercetin or sham injections. Hair regrowth was observed in lesional areas in all the quercetin-treated mice, but in none of the sham-treated mice.

In addition, non-alopecic C3H/HeJ mice were heat-treated to induce alopecia, along with quercetin or sham injections. Whereas 24% of the heat-treated mice with sham injections developed alopecia, none of the mice receiving quercetin injections did. As expected, the level of HSP70 expression in quercetin-treated areas was comparable to control. Furthermore, we showed that systemic delivery of quercetin by intraperitoneal injections prevented/reduced spontaneous onset of AA.

Our results demonstrated that quercetin provided effective treatment for AA as well as prevention of onset of AA in the C3H/HeJ model, and warrant further clinical studies to determine whether quercetin may provide both treatment for preexisting AA and prevention of recurrent AA. The ready availability of quercetin as a dietary supplement may lead to increased patient compliance and positive outcomes for AA.

Introduction
Alopecia areata (AA) is a non-scarring, autoimmune hair loss disorder (Alkhalifah et al. 2010a). AA often has a sudden onset (Gilhar and Kalish 2006) and may be acute, recurrent, or chronic (Gilhar and Kalish 2006; Garg and Messenger 2009). AA is a T-cell-mediated inflammatory disorder specific for the hair follicle (HF); affected skin appears normal, with no apparent signs of inflammation (Gilhar et al. 2007).

Clinical presentation varies considerably (McElwee et al. 2003), but a well-defined, circumscribed patch is most common initially (Dudda-Subramanya et al. 2007). AA can occur on any region of hair-bearing skin, but is found on the scalp 90% of the time (Wasserman et al. 2007). AA has an incidence of 0.1–0.2% in the general population with a lifetime risk of 1.7% (Safavi et al. 1995). Likelihood of onset is irrespective of sex or age (Safavi et al. 1995); however, initial patches present before age 20 in most cases (Price 1991). Scalp hair loss may impose a high psychosocial burden on patients, especially in severe and chronic situations (Safavi et al. 1995; Dudda-Subramanya et al. 2007). AA can occasionally progress to alopecia totalis (AT), loss of all scalp hair; or alopecia universalis (AU), loss of all body hair (Kos and Conlon 2009).

Histologically, AA is characterized by peri- and intra-follicular mononuclear cell infiltration of the HF (Gilhar et al. 2007). HFs susceptible to the infiltrate seem to be in the growth phase (anagen) and undergoing active melanogenesis (Gilhar et al. 2007). The mononuclear infiltrate is composed of both CD4+ and CD8+ T lymphocytes (McElwee et al. 2003; Wasserman et al. 2007). CD4+ T cells predominate around the HF, while CD8+ T cells predominate within the HF (Gilhar et al. 2007; Cetin et al. 2009).

AA is thought to develop as a result of a loss of the immune privilege (IP) of the HF (Paus et al. 2003; Arck et al. 2008; Gilhar 2010). Normally, the lower portion of the HF is immunoprivileged due to (1) the absence of major histocompatibility complex (MHC) class II expression, (2) very low levels of MHC class I expression, (3) active suppression of natural killer (NK) cells, and (4) a decreased density of antigen-presenting cells (APCs) such as Langerhans cells (Gilhar and Kalish 2006; Gilhar et al. 2007). However, as the APCs present the antigens, responsive lymphocytes are activated and therefore migrate to and infiltrate the HFs. These inflammatory infiltrates are deleterious to the HFs (McElwee et al. 2003; Arck et al. 2008).

Currently, corticosteroids are the most commonly used anti-inflammatory therapy for acute AA; they can be administered topically, intralesionally, or systemically (Wasserman et al. 2007). Other therapies in use include topical sensitizers, dithranol (anthralin), photochemotherapy, minoxidil, and immunomodulators including some biologics (Wasserman et al. 2007; Garg and Messenger 2009). In addition, some alternative and complementary therapies have been evaluated (van den Biggelaar et al. 2010). However, no existing therapy for AA is known to alter the course of disease or prevent recurrence (Garg and Messenger 2009). High relapse rates, varying levels of efficacy, and concerns about adverse effects warrant the search for alternative treatments and preventative therapies for recurrent AA.

One potential therapy is the natural compound quercetin, which is known for its anti-inflammatory properties (Boots et al. 2008). Quercetin (3,3′,4′,5,7-pentahydroxyflavone, also called quercetine, sophretin, or meletin) is a bioflavonoid. As an anti-inflammatory, quercetin has been observed to inhibit the activation of nuclear factor kappa-B (NF-κB), a transcription factor that stimulates the production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and the interleukins IL-1, IL-2, and IL-6 (Nam 2006; Bhaskar et al. 2011).

Heat shock proteins (HSPs) are known to play a role in the inflammatory response (Pockley et al. 2008). HSPs can act as intercellular signaling molecules promoting the production of inflammatory cytokines and adhesins; they can also deliver maturation signals and present peptides to APCs (Roberts et al. 2010). Heat shock protein 70 (HSP70 or HSPA1A/B), when found outside the cell, can serve as a “danger signal” triggering inflammation (Pockley et al. 2008). Indeed, we have previously demonstrated a correlation between AA and HSP70 expression in a mouse model; increased HSP70 expression was observed in lesional skin as compared to control (Wikramanayake et al. 2010). Furthermore, HSP70 has been shown to interact with immunoregulatory T cell populations (Pockley et al. 2008).

Thus, in this study, we tested the effects of quercetin, an anti-inflammatory and known HSP70 inhibitor (Wang et al. 2009), in the C3H/HeJ mouse model for AA.

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Quercetin is found in many foods. Rich sources of quercetin include broccoli, parsley, onions, apples, grapes, dark berries, cherries, raisins, cabbage, beans, tomatoes, tea, and red wine (Erdman et al. 2007; Egert et al. 2011; Lee et al. 2011).