Atopic dermatitis is an allergy that affects an average of about 5% of the general population, with symptoms closely related to social stress. In socially active adults, the disease often becomes chronic. In the affected areas, infiltrating immune cells secrete inflammatory cytokines, which contribute to the development of symptoms. While these cytokines normally play a protective role against pathogenic microbes under physiological conditions, their excessive and prolonged release in atopic dermatitis disrupts the epidermal barrier, the skin’s first line of defense against environmental factors. Inflammatory responses in atopic dermatitis are initially triggered by T cells, followed by other immune and tissue cells. In a new study, scientists focused on Bach2, a nuclear protein essential for maintaining normal T-cell function through its binding to Maf recognition elements (MAREs).
It plays an important role in coordinating the activation and repression of transcription by MafK, a close cousin of the transcription factor Nrf-2, well known to control the expression of cellular protective proteins (e.g. Hsp70, Trx-1) and detoxifying and antioxidant enzymes (e.g. HO-1, GSTp, SOD2, etc.). Bach2 also promotes the nuclear import of actin from the cytoplasm, which serves as an additional scaffold to coordinate the assembly of various transcriptional complexes. In primary and transformed CD4+ T cells, Bach2 overexpression counteracted the induction of interleukin-2 (IL-2) expression induced by the T-cell receptor (TCR)/CD28 or PMA/ionomycin, whereas Bach2 silencing had the opposite effect. Bach2 binds to multiple Maf recognition element-like sites on the proximal IL-2 promoter in a competitive manner with AP-1, and thereby represses AP-1-driven IL-2 expression.
Since IL-2 and its receptor have been found to be increased in both circulating immune cells and serum in the majority of subjects with atopic dermatitis, it is reasonable to think that Bach2 affects the expression of this cytokine and that it could be a cellular target to exploit. To investigate its role in atopic dermatitis, the researchers generated three types of mouse models: mice in which Bach2 levels can be monitored using a fluorescent tag, transgenic mice with T cells expressing high levels of Bach2 (Bach2 Tg mice), and knockout mice lacking Bach2 in T cells (Bach2 KO mice). The scientists found that T cells with low and/or intermediate levels of Bach2 accumulate in areas affected by atopic dermatitis; Bach2 Tg mice do not develop atopic dermatitis, while Bach2 KO mice have severe and prolonged (chronic) symptoms.
Finally, Bach2 KO mice have a more fragile skin barrier, both functionally and structurally. Bach2 levels are dynamically regulated together with the state of T cells. Mice deficient in Bach2 specific to T cells showed more severe inflammatory responses to the hapten and had prolonged inflammation with T cells expressing higher levels of IL-13 in the skin and IFN-γ and IL-13 in the lymph nodes draining the skin. The results of the study suggest that precise modulation of Bach2 levels in T cells may help reduce the chronicity of atopic dermatitis, highlighting the potential for the development of a new therapeutic approach aimed at Bach2 regulation in T cells. One option could be to use molecules that either induce Bach2 expression (also among known immunomodulatory drugs), or that induce cellular signals capable of activating Bach2 function.
For example, it is known that in leukemia cells the Bcr-Abl oncogenic chimaera triggers several signaling platforms (Ras-ERK, JAK-STAT and PI3K-Akt), to promote cellular proliferation and apoptosis suppression. Bach2 is target for the PI3K and ribosomal kinases (Rsk1/2); once phosphorylated on residue 252, it cannot enter the nucleus to activate transcription. Therefore, PI3K-Akt-Rsk signaling upstream of Bach2 could be a possible therapeutic target to suppress in order to allow Bach2 specific activities. Known small inhibitors of these kinases are already available and studied in the clinical setting (PI3K inhibitors as anticancers and immune checkpoint therapy adjuvants). Therefore, enhancing Bach2 activity would represent the new avenue to suppress the onset or the progression of atopic dermatitis.
- edited by Dr. Gianfrancesoc Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Omori-Miyake M et al. J Allergy Clin Immunol. 2025; in press.
Lahmann A, Kuhrau J et al. Immunol. 2019; 202(8):2229-39.
Jang E, Lee HR et al. J.BMB Rep. 2017 Sep; 50(9):472-477.
Igarashi K, Ochiai K et al. Immunol Rev. 2014; 261(1):116-25.
