TLR2 Regulates Hair Follicle Cycle and Regeneration via BMP Signaling.

  1. Luyang Xiong
  2. Irina Zhevlakova
  3. Xiaoxia Z. West
  4. Detao Gao
  5. Rakhylia Murtazina
  6. Anthony Horak
  7. J. Mark Brown
  8. Iuliia Molokotina
  9. Eugene A. Podrez
  10. Tatiana V. Byzova

  • Curated by eLife

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    eLife assessment

    In this manuscript by Xiong L et al., through TLR2, the authors have uncovered an important link between innate immune signaling and hair regeneration. The authors provide convincing evidence supporting the critical roles of TLR2 in sensing CEP levels in hair follicles, counteracting the action of BMP signaling, and facilitating the activation of HFSCs during the hair cycle and wound repair. Importantly, the authors also propose that decreased CEP production and TLR2 expression might be factors contributing to the decreased hair regeneration associated with age-related and obesity-related hair thinning and hair loss phenotypes.

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Abstract

The etiology of hair loss remains enigmatic, and current remedies remain inadequate. Transcriptome analysis of aging hair follicles uncovered changes in immune pathways, including Toll-like receptors (TLRs). Our findings demonstrate that the maintenance of hair follicle homeostasis and the regeneration capacity after damage depends on TLR2 in hair follicle stem cells (HFSCs). In healthy hair follicles, TLR2 is expressed in a 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.

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  1. eLife

    eLife assessment

    In this manuscript by Xiong L et al., through TLR2, the authors have uncovered an important link between innate immune signaling and hair regeneration. The authors provide convincing evidence supporting the critical roles of TLR2 in sensing CEP levels in hair follicles, counteracting the action of BMP signaling, and facilitating the activation of HFSCs during the hair cycle and wound repair. Importantly, the authors also propose that decreased CEP production and TLR2 expression might be factors contributing to the decreased hair regeneration associated with age-related and obesity-related hair thinning and hair loss phenotypes.

  2. eLife

    Joint Public Review:

    This paper's strengths are the interesting analysis of TLR signaling in hair follicle stem cell activation and the striking phenotype of the TLR2 cKO mice (but note below). The functional interrogation parts using HFSC-specific TLR2 genetic deletion are solid, and an endogenous regulator, CEP, is identified. The experiments reported in this manuscript are well-designed and presented. The authors provided extensive evidence supporting the roles of TLR2 signaling in regulating hair follicle stem cell functions. Importantly, the findings from this paper may have sustained impacts on our understanding of the roles of innate immunity in regulating tissue regeneration in the absence of inflammation.

    The main evidence for the mechanistic analysis is based on fluorescence using immunohistochemistry, and here the expression analysis is not convincing. In addition, additional assays beyond immunolandscaping are needed to confirm the findings. The reviewers felt that your data substantiating the mechanism of interaction between TLR2 and BMP pathway needs bolstering.

  3. Version 2 published on bioRxiv
  5. Version 1 published on bioRxiv