We normally lose from 50 to 100 hairs every day. Whether we notice it or not, lost hair is replaced with newly growing ones all the time. So far, we know of several factors that can disrupt this balance and lead to significant hair loss; including heredity, hormonal changes, infectious agents, medications (for instance drugs for cancer treatment), and stressful events. But did you know that an aberrant immune response can also cause hair loss? This condition is called alopecia areata. Nowadays, it is considered an autoimmune disease as this condition results from lack of immune tolerance towards hair follicles (HFs). In today’s blog we ask, could the immune system also contribute to hair growth?
To answer this question, Zhi Liu and colleagues focused on regulatory T cells (Tregs) that maintain immune homeostasis by preventing immune response against self-antigens. In addition to this, Tregs can promote repair and regeneration in the skin, cardiac muscle, and other tissues by communicating with tissue resident stem cells (but we don’t know how exactly, yet). The researchers also focused on glucocorticoids, which are steroid hormones produced in response to stress or injury in the adrenal gland and other tissues, particularly in the skin. Across different tissues, glucocorticoid receptors (GRs) are expressed in most cells, including Tregs.
Taking this information together, the authors hypothesized that glucocorticoids might be important for communication between skin resident Tregs and hair follicular stem-cell (HFSC).
Zhi Liu and colleagues worked on a mouse model here. First, they measured the expression levels of genes encoding the GRs and other steroid hormone receptors in skin-resident Tregs compared to Tregs isolated from skin-draining lymph nodes and spleen. Skin-resident Treg cells showed the highest expression of GR genes amongst the steroid hormone receptors.
The obtained result logically led to the next step – examining the level of glucocorticoids in the skin during hair regeneration. To check this, researchers applied depilation-induced hair regrowth models. Interestingly, to completely remove the trimmed mice hair they literally used the depilatory cream – Nair. Depilated mice gradually increased glucocorticoid levels in the skin during the first 48 hours after the procedure.
They then generated mice whose skin resident Tregs lacked GRs. The aim of this was to measure the ability to regrow hair after depilation compared to wild-type mice. Two weeks after depilation, GR knockout mice showed less than 20% hair regrowth (both hair amount and HFs length) whereas the mice with normal GR genes expression completely regrew their hair. With the above experiments, the authors concluded that glucocorticoids are required for skin Treg-mediated hair regeneration.
However, the question of how skin Tregs communicate with HFSC was still open.
To explore direct Tregs-HFSC cross-talk, authors deleted GRs in a mouse model but that did not affect Treg immune suppression and immune homeostasis in the skin. The authors speculated that glucocorticoids are needed for skin resident Tregs to produce, let’s say factors X, that activate HFSC. To investigate the Tregs–HFSC “conversation”, the scientists now used a computational software. They compared RNA-seq transcriptome data of wild-type mice and GR knockout mice and noticed a significant difference in the Tgfb3-Tgfbr pair (TGF-β3 is a protein that controls the growth and division of cells).
The authors further studied the role of TGF-β3 in vivo as a messenger in providing hair growth. They injected TGF-β3-neutralizing antibodies into the skin of wild mice and depilated them. They observed a delay in hair growth in the injection site compared with the control. In mice without GRs authors successfully rescued hair regrowth defects by injecting TGF-β3 intradermally.
The final confirmatory experiment was done by generating the TGF-β3 knockout mice model. Such mice had a severe delay of natural hair regrowth compared with normal mice confirming previous results. So, the previously unknown factor X in skin-resident Tregs–HFSC interaction, turns out to be TGF-β3.
Now let’s put all the pieces together. Hair depilation in mice induces glucocorticoid production in the skin. Skin-resident Tregs in response to elevated glucocorticoids level start producing TGF-β3. This promotes HFSC activation, proliferation, and finally hair growth. Interesting, isn’t it? This study also means that, once again, Tregs could be therapeutically targeted and manipulated, this time for tissue regeneration.
Till now, researchers have found secret roles of the immune system in almost all aspects of human life. We can only imagine what else is our immune system responsible for?
Liu Z, Hu X, Liang Y, Yu J, Li H, Shokhirev MN, Zheng Y. Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche. Nat Immunol. 2022 Jul;23(7):1086-1097. doi: 10.1038/s41590-022-01244-9.
Article author: Taras Baranovskyi. Taras is a medical doctor at Immunotherapy Clinic in Kyiv, Ukraine. His research is focused on developing new approaches for overcoming the antimicrobial resistance of Klebsiella pneumoniae. Also, Taras is a part of a team which spreads knowledge of immunology through the ‘Cup of Immunology’ project.
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