The role of macrophages and mast cells in stress related hair loss (written for my Trichology fellowship)

Stress related hair loss is a widespread concern for many people, with effective treatment options still developing (Xiao et al., 2024).

To better understand how stress can result in hair loss, I’m going to explore the relationship between stress and immune system activity, focusing on the role of macrophages and mast cells in stress-related hair loss.

Accumulated evidence now supports the idea that the sympathetic nervous system (SNS) regulates the immune system through catecholamines at regional, local, and systemic levels (Arck et al., 2006). Physical and mental stress can activate the sympathetic nervous system to varying degrees, inducing the release of noradrenaline at the nerve ends of the SNS. The release of noradrenaline can create a pro-inflammatory effect through the increased release of immune cells (Yang et al., 2012).

Stress is one of the primary causes of hair loss due to increased cortisol levels having a negative impact on the hair follicle formation mechanisms. Stress is considered one of the main causes of Telogen Effluvium. However, stress can also exacerbate hair loss caused by other factors, such as endocrine imbalances and immunological responses. A cycle can be created, whereby stress caused from hair loss can further continue the loss (Gokce et al., 2022).

The brains systemic response to stress is signalled through mediators that primarily involve the hypothalamic-pituitary-adrenal (HPA) axis, SNS, and signal through a series of pathways until reaching the skin. Macrophages, mast cells, and even keratinocytes are among some of the cells that participate in the immune response to stress, creating the body’s neuroendocrine-immune network (Zhang et al., 2024).

The appendages of the skin can also replicate the same mediators that are seen during a systemic response to stress and have established a fully functional peripheral equivalent of the systemic stress activated HPA axis. This was shown in micro-dissected, organ-cultured human scalp hair follicles that demonstrated a fully functional peripheral HPA axis equivalent (Arck et al., 2006). 

Macrophages are a type of white blood cell that helps initiate immune response and destroy foreign bodies by engulfing them. They play a key role in developing specificity in the immune response through their processing of foreign bodies which helps identify these bodies to lymphocytes (Encyclopaedia Britannica, 2025).

Mast cells are a type of immune cell derived from bone marrow. Mast cells are found in areolar tissue throughout the entire body. Their role involves initiating inflammatory response (Fong & Crane, 2023). However, under ideal low stress conditions, mast cells contribute to the ‘immune privilege’ of the hair follicle by releasing immune mediators, which, at normal levels, reduce and suppress inflammation and modulate immune cell activity around hair follicles (Kiselev & Park, 2024). When mast cells are activated by immune mechanisms, they go through a process called degranulation, whereby, they release inflammatory mediators, such as cytokines, into extracellular space. Histamines are considered one of the most important cytokines released (Fong & Crane, 2023). Mast cells are also particularly rich in TNF-alpha which is known to be a potent inhibitor of hair follicle growth and an important player in the pathophysiology of inflammatory hair diseases (Philpott et al., 1996).

Animal studies have shown an association between chronic stress and hair growth cessation, increased granulation of mast cells, and peri-follicular inflammation. Stress mediators such as, substance P, adrenocorticotrophic hormone, prolactin, and cortisol can also impede hair growth during this presentation (Gokce et al., 2022).

During psychological stress, sensory nerves in the skin release calcitonin gene-related peptide (CGRP) that causes mast cell degranulation via binding to the receptors on mast cells. This was evident within the connective tissue sheath of hair follicles, indicating one of the factors in neurogenic inflammation at this level.

Increased mast cell count may contribute to reduced stimulation of dermal papilla cells and the inhibition of hair growth. This, and the stimulation of mast cell degranulation may be one of the aspects in understanding stress induced Telogen Effluvium and Alopecia Areata (Zhang et al., 2024).

During anagen, hair follicles are protected from unwanted immune cell activity through a mechanism called ‘immune privilege’ (Gokce et al., 2022). An imbalance between pro-inflammatory and anti-inflammatory signals can alter follicular immune privilege, leaving the follicles vulnerable to hair loss (Kiselev & Park, 2024). The exact cause(s) of immune privilege breakdown isn’t clear, but mast cell degranulation may be a contributing factor among other mechanisms (Gokce et al., 2022).

Macrophages have receptors on their surface for toll-like receptors, which are the initiators of inflammatory response. Macrophages are one of the producers of cytokines which induce inflammation, as well as activating B and T, immune cells (IAT, 2022).

Macrophages and mast cells contribute significantly to the hair follicle growth cycle. Macrophages do so via contributing to the modulation of the different growth phases. During anagen, they promote proliferation, resulting in hair growth. In catagen, they facilitate the cessation of growth and initiate follicle regression. More importantly, macrophages are instrumental to maintaining and regulating the telogen phase through JAK-STAT pathways.

Macrophage numbers are higher in early-mid telogen and decrease until the onset of anagen. Experiments in mice showed that macrophage ablation during telogen can induce transition to anagen (Kiselev & Park, 2024).

Upregulated perifollicular mast cell degranulation downregulates keratinocyte proliferation and upregulates apoptosis of follicular keratinocytes via mechanisms that prematurely trigger follicular regression into catagen (Arck et al., 2006).

This demonstrates how increased macrophages and mast cells due to stress/immune triggers can lead to the development of stress-related hair loss.

Stress in mice has been shown to upregulate the number of apoptotic cells in the hair follicle bulge, attracting infiltrates of dense, potentially auto-destructive perifollicular cells, consisting predominantly of activated macrophages. Due to this bulge region of the hair follicle being the crucial epithelial stem-cell region, this subjects the hair follicle to the risk of irreversible damage by induction of programmed hair follicle organ deletion (Arck et al., 2006).

At a local inflammation site, the SNS response often triggers an anti-inflammatory mechanism through direct neurotransmitter influence on immune cells. This can induce local promotion of the anti-inflammatory M2 phenotype macrophages, via beta-2 adrenergic receptors for catecholamines such as noradrenaline. However, other alpha-adrenergic receptors for catecholamines can be pro-inflammatory, such as, alpha-2 adrenergic receptors which stimulate macrophages of a reactive oxygen species, such as M1 phenotype macrophages (Pongratz & Straub, 2014). This appears to be the phenotype macrophages adopt during stress related hair loss. However, the beta-2 adrenergic receptor, under the influence of elevated noradrenaline, may respond differently as detailed below.

One study in a murine model that explored whether stress-induced hair loss was related to an imbalanced immune microenvironment, discovered a significant increase in macrophages after stress was induced. It confirmed that elevated noradrenaline, induced macrophage polarisation towards M1 phenotype macrophages (pro-inflammatory) through the noradrenaline receptor, beta-2 adrenergic receptor. The importance of macrophages in stress-related hair loss was highlighted by their clearance resulting in the cessation of hair shedding (Xiao et al., 2024).

In alopecia areata, a collapse of immune privilege is witnessed in anagen bulbs and perifollicular mast cells show pro-inflammatory properties and interact with CD8+ T cells, that respond to autoantigens (Gokce et al., 2022). Compared to healthy skin, alopecia areata lesions have significantly higher presence of mast cells (IAT, 2021). It may also be considered of interest that alopecia areata patients are, reportedly, more likely to present with psychological stress, such as anxiety and depression than healthy individuals (Ma et al., 2023). Itching can also be induced by stress, through mast cell activation (Zhang et al., 2024), which may be considered interesting due to many patients complaining of itching on areas preceding alopecia areata or during telogen effluvium.

To summarise, the gathered evidence demonstrates the crucial facilitating roles that macrophages and mast cells play during stress-induced hair loss. These two immune cells, that under normal circumstances aid in the protection of hair follicle, through immune privilege, turn into saboteurs under immune mediated responses to stress. This leads to the release of pro-inflammatory cytokines and the polarization towards pro-inflammatory macrophage phenotypes, causing; premature hair growth cycle regression, inhibiting growth signals, negatively impacting the structural integrity of the hair follicle, and in extreme cases leading to hair follicle destruction through mechanisms that attack follicular stem cells.

We could speculate that further studies into therapeutic manipulation of immune pathways, such as, modulating macrophage phenotypes and abrogation of mast activation, as well as holistic approaches to managing and regulating stress, could provide pioneering therapies for the treatment of stress-related hair loss and emphasise the importance of understanding the hair follicle immune microenvironment and its relationship to stress.

References

Arck, P. C., Slominski, A., Theoharides, T. C., Peters, E. M. J., & Paus, R. (2006). Neuroimmunology of Stress: Skin Takes Center Stage. Journal of Investigative Dermatology, 126(8), 1697–1704. https://doi.org/10.1038/sj.jid.5700104 

Fong, M., & Crane, J. S. (2023). Histology, Mast Cells. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK499904/ 

Gokce, N., Basgoz, N., Kenanoglu, S., Akalin, H., Ozkul, Y., Ergoren, M. C., Beccari, T., Bertelli, M., & Dundar, M. (2022). An overview of the genetic aspects of hair loss and its connection with nutrition. Journal of Preventive Medicine and Hygiene, 63(2 Suppl 3), E228–E238. https://doi.org/10.15167/2421-4248/jpmh2022.63.2S3.2765 

International Association of Trichologists (IAT). (2022) Body systems. International association of Trichologists course, MOD 2, 51-52.

International Association of Trichologists (IAT). (2021) Hair loss and scalp problems. International association of Trichologists course, MOD 9 and 10, 37.

Kiselev, A., & Park, S. (2024). Immune niches for hair follicle development and homeostasis. Frontiers in Physiology, 15. https://doi.org/10.3389/fphys.2024.1397067

Ma, Y., Sun, Z., Li, Y., & Xu, H. (2023). Oxidative stress and alopecia areata. Frontiers in Medicine, 10, 1181572. https://doi.org/10.3389/fmed.2023.1181572

Philpott, M. P., Sanders, D. A., Bowen, J., & Kealey, T. (1996). Effects of interleukins, colony-stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible role for interleukin-1 and tumour necrosis factor-alpha in alopecia areata. The British journal of dermatology, 135(6), 942–948. https://doi.org/10.1046/j.1365-2133.1996.d01-1099.x 

Pongratz, G., & Straub, R. H. (2014). The sympathetic nervous response in inflammation. Arthritis Research & Therapy, 16(6). https://doi.org/10.1186/s13075-014-0504-2

The Editors of Encyclopaedia Britannica (2025, March 22). macrophage. Encyclopedia Britannica. https://www.britannica.com/science/macrophage

Xiao, X., Gao, Y., Yan, L., Deng, C., Wu, W., Lu, X., Lu, Q., Zhong, W., Xu, Y., Zhang, C., Chen, W., & Huang, B. (2024). M1 polarization of macrophages promotes stress‐induced hair loss via interleukin‐18 and interleukin‐1β. Journal of Cellular Physiology, 239(4). https://doi.org/10.1002/jcp.31181

Yang, j. H., Lee, E. O., Kim, S. E., Suh, Y., & Chong, Y. H. (2012). Norepinephrine differentially modulates the innate inflammatory response provoked by amyloid-β peptide via action at β-adrenoceptors and activation of cAMP/PKA pathway in human THP-1 macrophages. Experimental Neurology, 236(2), 199–206. https://doi.org/10.1016/j.expneurol.2012.05.008

Zhang, H., Wang, M., Zhao, X., Wang, Y., Chen, X., & Su, J. (2024). Role of stress in skin diseases: A neuroendocrine-immune interaction view. Brain, Behavior, and Immunity, 116, 286–302. https://doi.org/10.1016/j.bbi.2023.12.005