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Dysfunction in hair follicles and loss of the capacity for hair growth is a perhaps surprisingly complex aspect of aging and disease. For all the the basic mechanisms of hair growth are well-investigated, the hair follicle is a complex structure, and hair growth involves the collaboration of many cell types, activities, and signaling that shifts over time as the follicle progresses through the stages of growth. It has proven to be hard to pin down any one specific mechanism as vital, and it may turn out to be the case that no one specific mechanism is the key to preventing loss of hair with advancing age and other circumstances.
Nonetheless, researchers continue to search for that one specific mechanism that may reverse age-related loss of hair follicle function and hair growth. In today’s open access paper, researchers argue for innate immune involvement to be important, mediated by toll-like receptor 2 (TLR2). Level and activity of TLR2 both decline with age, while delivery of a suitable native ligand that interacts with TLR2 produces improved regeneration of hair follicles and hair regrowth following injury in mice. Whether this approach will also work to reverse hair thinning and hair follicle dysfunction in old, uninjured animals remains to be seen.
TLR2 regulates hair follicle cycle and regeneration via BMP signaling
Hair follicles (HFs) represent one of the best examples of mini-organs with the ability to regenerate throughout life, which, in turn, relies on the proliferation and differentiation of HF stem cells (HFSCs) within hair bulge. The cyclic renewal of HFs is orchestrated by the interplay between inhibitory and stimulatory signals. Despite the immune privileged status of HFs, they have a unique microbiome and immune system, including resident macrophages and other immune cells. Components of the HF immune system have been implicated in regulating the HF cycle and its regeneration. Given their exposure to pathogens, HFs are equipped with innate immune receptors, particularly Toll-like receptors (TLRs), which detect and respond to pathogens by stimulating the secretion of defensins.
TLRs play a key role in recognizing and responding to either pathogen-associated molecular patterns or damage-associated molecular patterns, mediating the cytokine response. However, the role of TLRs extends beyond this function, as they have been shown to directly promote tissue regeneration and homeostasis in multiple tissues, particularly in stem and progenitor cells.
Multiple reports connect altered HFs’ immunity to hair loss, including a breakdown of immune privilege in alopecia areata. Likewise, androgen, which is tightly linked to TLR activation, was shown to influence the innate immunity of HFs in androgenic alopecia. The decline of innate immunity processes due to aging or conditions like obesity is widely recognized and these conditions are causatively associated with hair thinning and loss. Alopecia patients often have higher body weight index and weight compared to healthy individuals. Increased body weight index is linked to more significant hair loss severity in adults and a higher prevalence of hair disorders in children and adolescents. Mouse models support these findings, showing that activation of innate immunity through pathogen signals might lead to alopecia and that high-fat diets inducing obesity cause hair thinning through HFSC depletion.
Transcriptome analysis of aging hair follicles uncovered changes in immune pathways, including TLRs. Our findings demonstrate that the maintenance of hair follicle homeostasis and the regeneration capacity after damage depend on TLR2 in hair follicle stem cells (HFSCs). In healthy hair follicles, TLR2 is expressed in a hair cycle-dependent manner and governs HFSCs activation by countering inhibitory BMP signaling. Hair follicles in aging and obesity exhibit a decrease in both TLR2 and its endogenous ligand carboxyethylpyrrole (CEP), a metabolite of polyunsaturated fatty acids. Administration of CEP stimulates hair regeneration through a TLR2-dependent mechanism. These results establish a novel connection between TLR2-mediated innate immunity and HFSC activation, which is pivotal to hair follicle health and the prevention of hair loss and provide new avenues for therapeutic intervention.