DOI: 10.1002/jcp.31181

In a groundbreaking study recently published in the “Journal of Cellular Physiology,” researchers have uncovered the influential role played by specialized immune cells—macrophages—in stress-induced hair loss, paving the way for potential new treatments addressing this common condition. This research is especially timely, given the increased stress levels in today’s society and the corresponding rise in individuals experiencing its impact on hair health.

Stress-induced hair loss, medically known as telogen effluvium, has long baffled scientists and healthcare providers, with its underlying mechanisms shrouded in mystery and effective treatment options notably scarce. However, this study spearheaded by Xiao Xing and his team from The Seventh Affiliated Hospital of Sun Yat-sen University, among others, sheds light on the neural (stress)-endocrine (norepinephrine – NE)-immune (macrophages) axis that seems to play a critical role in how stress triggers hair shedding (Xiao et al., 2024).

The researchers initially pinpointed a significant increase in macrophages within the skin of a stress-challenged mouse model. Notably, when macrophages were cleared, the mice were rescued from both stress-induced hair shedding and depletion of hair follicle stem cells (HFSCs), indicating a direct involvement of these immune cells in the hair loss process.

The intrigue deepened when further flow cytometry analysis revealed not just any macrophages, but an elevated presence of M1 phenotype macrophages—one of the two primary polarization states of these versatile cells known for their pro-inflammatory actions (Shapouri-Moghaddam et al., 2018; Locati et al., 2020). Connecting the dots between stress and this immune response, the team found increased levels of the hormone norepinephrine (NE) in the blood of stressed mice. This NE surge was found to induce M1 polarization via the β-adrenergic receptor, Adrb2.

Diving deeper with transcriptome, enzyme-linked immunosorbent assay (ELISA), and western blot analyses, Xiao and colleagues also revealed a significant upregulation in the NLRP3/caspase-1 inflammasome signaling pathway in NE-treated macrophages, leading to higher levels of interleukin 18 (IL-18) and interleukin 1 beta (IL-1β). These interleukins, as confirmed by the study, have the capacity to induce apoptosis among HFSCs.

But the researchers didn’t stop at determining the causality of the problem; they also explored solutions. Inhibition of the stress hormone receptor Adrb2 with the drug ICI118551 successfully reversed the upregulation of the harmful signaling and interleukins, suggesting possible therapeutic intervention routes.

Crucially, when IL-18 and IL-1β signals were blocked, not only was the depletion of HFSCs in skin organoid models reversed, but there was also a significant reduction in stress-induced hair shedding in mice. This dramatic result highlights these interleukins as potential targets for treating stress-related hair loss (Xiao et al., 2024).

The study authors hypothesize that under stress, the body’s increased release of NE leads to a higher polarization of M1 macrophages, which, through NLRP3/caspase-1 signaling, churn out IL-18 and IL-1β. These interleukins then harm the HFSCs, leading to hair loss. This discovery opens up promising avenues for hair loss therapy that focus on altering the immune system’s behavior rather than targeting the hair follicles directly.

The implications of the study are considerable, offering not only a new understanding of the pathological process underlying stress-induced hair loss but also a beacon of hope for those looking for effective treatments. It also underscores the multifaceted roles that macrophages play, from their involvement in tissue repair and regeneration (Chu et al., 2019; Weber et al., 2016) to their ability to influence hair follicle behavior (Wang et al., 2017; Müller-Röver et al., 2001).

Previous research has focused on different aspects of hair follicle biology and hair loss disorders (Cotsarelis, 2006; Stefanato, 2010; Pratt et al., 2017), but looking at the problem through the lens of the immune system marks a significant pivot in approach. This strategy builds upon the existing notion of the skin as an immune organ, where interactions between the immune system and skin resident cells are essential for skin tissue homeostasis and function (Nestle et al., 2009; Englander et al., 2023).

With these findings, new therapeutic interventions may be designed to restore balance in the skin’s immune microenvironment. The prospect of macrophage modulation or specific blockade of IL-18 and IL-1β as a treatment for stress-induced hair loss could be a game-changer for countless individuals dealing with this condition.

In conclusion, this study not only intertwines the neural, endocrine, and immune pathways in the context of hair loss but also articulates the potential for therapeutic interventions that were previously unexplored. As the research progresses, the development of targeted treatments could soon alleviate the distress caused by stress-related hair loss conditions.

References

1. Xiao Xing et al. (2024). M1 polarization of macrophages promotes stress-induced hair loss via interleukin-18 and interleukin-1β. Journal of Cellular Physiology.
2. Shapouri-Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S. A., Mardani, F., Seifi, B., Mohammadi, A., Afshari, J. T., & Sahebkar, A. (2018). Macrophage plasticity, polarization, and function in health and disease. Journal of Cellular Physiology, 233, 6425-6440.
3. Locati, M., Curtale, G., & Mantovani, A. (2020). Diversity, mechanisms, and significance of macrophage plasticity. Annual Review of Pathology: Mechanisms of Disease, 15, 123-147.
4. Chu, S. Y., Chou, C. H., Huang, H. D., Yen, M. H., Hong, H. C., Chao, P. H., Wang, Y. H., Chen, P. Y., Nian, S. X., Chen, Y. R., Liou, L. Y., Liu, Y. C., Chen, H. M., Lin, F. M., Chang, Y. T., Chen, C. C., & Lee, O. K. (2019). Mechanical stretch induces hair regeneration through the alternative activation of macrophages. Nature Communications, 10, 1524.
5. Wang, E. C. E., Dai, Z., Ferrante, A. W., Drake, C. G., & Christiano, A. M. (2019). A subset of TREM2(+) dermal macrophages secretes oncostatin M to maintain hair follicle stem cell quiescence and inhibit hair growth. Cell Stem Cell, 24, 654-669.
6. Weber, C., Telerman, S. B., Reimer, A. S., Sequeira, I., Liakath-Ali, K., Arwert, E. N., & Watt, F. M. (2016). Macrophage infiltration and alternative activation during wound healing promote MEK1-induced skin carcinogenesis. Cancer Research, 76, 805-817.
7. Müller-Röver, S., Foitzik, K., Paus, R., Handjiski, B., van der Veen, C., Eichmüller, S., McKay, I. A., & Stenn, K. S. (2001). A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. Journal of Investigative Dermatology, 117, 3-15.
8. Cotsarelis, G. (2006). Epithelial stem cells: A folliculocentric view. Journal of Investigative Dermatology, 126, 1459-1468.
9. Nestle, F. O., Di Meglio, P., Qin, J. Z., & Nickoloff, B. J. (2009). Skin immune sentinels in health and disease. Nature Reviews Immunology, 9, 679-691.
10. Englander, H., Paiewonsky, B., & Castelo-Soccio, L. (2023). Alopecia areata: A review of the genetic variants and immunodeficiency disorders associated with alopecia areata. Skin Appendage Disorder, 9(5), 325-332.

Keywords

1. Stress-induced hair loss
2. M1 macrophage polarization
3. Hair follicle stem cell apoptosis
4. Interleukin treatment for alopecia
5. Norepinephrine and hair shedding