TLR2 Regulates Hair Follicle Cycle and Regeneration via BMP Signaling
Preprint posted on 16 August 2023 https://www.biorxiv.org/content/10.1101/2023.08.14.553236v1
A new miracle cure for hair loss? - How TLR2 signaling fuels hair cycling.
Selected by Marina SchernthannerCategories: cell biology, immunology
Background of the preprint
In maintaining tissue homeostasis and fueling repair, resident stem cells (SCs) heavily depend on cues from their microenvironment (niche). SC properties and niche composition vary across tissues and the skin has been established as an intriguing model to study SC-mediated regeneration.
In the bulge region of skin hair follicles resides a unique population of SCs – so-called hair follicle stem cells (HFSCs) – which have been characterized for their cyclical activity. HFSCs undergo bouts of proliferation (anagen), followed by periods of quiescence (telogen) several times during the lifetime of a mouse. However, it remains unclear to what extent their niche partners – and which ones in particular – might dictate or contribute to such cyclical activity.
In this preprint, Xiong, Zhevlakova and colleagues demonstrate how toll-like receptor 2 (TLR2) signaling in HFSCs fluctuates across hair cycle stages and becomes prominent at anagen onset. In line with that, TLR2 plays an important role in facilitating hair regeneration during wound repair in the skin and appears to drive HFSC proliferation via interfacing with the BMP pathway.
Key findings of the preprint
TLR2 is upregulated in HFSCs as they start to proliferate
As pointed out by the authors in this preprint, innate immunity sensing has been described to be less potent during aging and conditions such as obesity [1]. In line with that, this study reports a reduced expression of Tlr2 in murine skin hair follicles of aged mice or animals placed on a high-fat diet. Using a knock-in Tlr2-EGFP reporter mouse combined with transcriptional analyses, the authors not only found that Tlr2 expression was higher in HFSCs than epidermal SCs, but particularly abundant within SCs and their immediate progeny, while its expression decreased upon differentiation. TLR2 was upregulated at anagen onset, when HFSCs entered a proliferative state. Taken together, TLR2 levels strongly correlated with HFSC activity.
HFSC-specific ablation of TLR2 delays the hair cycle via a negative feedback loop with BMP signaling
Upon induction of HFSC-specific knockout of Tlr2 (TLR2-cKO) in K15-CrePR1 Tlr2Flox/Flox mice, anagen onset was significantly delayed, arguing for a role of TLR2 signaling in inducing HFSC proliferation. In subsequent immunofluorescence analyses the authors propose how this might be achieved via intersecting the BMP signaling pathway. Both the expression of BMP ligands (BMP7) as well as the downstream phosphorylation of Smad1/5/9 were upregulated in TLR2-cKO hair follicles, suggesting that active TLR2 signaling negatively regulates BMP signaling. As expected, when the authors inhibited BMP signaling in TLR2-cKO mice through administration of Noggin, HFSCs started to proliferate.
TLR2 in HFSCs mediates hair follicle regeneration in a wounding context
Corresponding to its role in activating HFSCs, Tlr2 expression was increased in intact, neighboring hair follicles following full thickness (punch) wounding in the murine back skin. Consequently, TLR2-cKO mice exhibited reduced skin pigmentation in wounded areas, fewer hair follicles per field and decreased proliferation, based on Ki67 signal, in hair follicles, but not necessarily a delay in wound closure in line with previous reports by this group [2]. Meanwhile, phosphorylation of Smad1/5/9 was elevated in wounded skin of TLR2-cKO animals compared to controls.
CEP acts upstream of HFSC-specific TLR2 in promoting hair follicle regeneration in wounds
Finally, the authors set out to investigate the signals upstream of TLR2 in the murine hair follicle. CEP, an endogenously produced ligand and product of poly-unsaturated fatty acid oxidation, serves as a major ligand for TLR2. While typically absent in healthy tissues, CEP tends to accumulate during inflammation and wound healing [3]. Using global and conditional TLR2-knockout mice as well as performing bone marrow transplantations, the authors demonstrated how CEP promoted hair follicle regeneration in wounds via TLR2 in HFSCs, but independently of TLR2-expressing immune cells. On a mechanistic level, treatment of HFSCs with CEP in vitro resulted in augmented expression of typical TLR2 target genes, including Nfkb2, Il1b or Il6, while inhibiting Bmp7. Thus, CEP via TLR2 directly suppresses BMP signaling in HFSCs, which in turn activates their proliferative potential.
In summary, Xiong, Zhevlakova and colleagues highlight a new role of TLR2 signaling in coordinating HFSC proliferation and anagen entry by negatively regulating the BMP pathway, which affect hair follicle regeneration following full thickness wounding.
What I like about this preprint
Toll-like receptors serve as pattern recognition receptors in innate immunity and recognize a myriad of viral, bacterial and cell-free ligands – which becomes particularly relevant during infection and inflammation. Nonetheless, a role for TLR signaling in the context of tissue regeneration has been highlighted in the bone marrow and intestine as well [4, 5]. In the murine skin, TLR7 actually serves as a marker to distinguish SCs of the interfollicular epidermis, which constantly proliferate to replenish the epidermal barrier and constitute a first line of defense [6]. Within the same tissue, HFSCs, in contrast, are cyclically active and reside in a quite different environment compared to epidermal SCs. TLR signaling within the HFSC compartment hence might serve very distinct functions that are developmentally regulated and coordinated with the dynamics of the hair cycle – a topic that has been poorly explored.
I was quite surprised to see how HFSC-specific deletion of TLR2 resulted in such a striking delay of hair cycling. It is well described how Wnt and BMP signaling shape the cyclical nature of HFSC activity and subsequent hair regeneration, but to find a pattern recognition receptor upstream of some of those pathways is intriguing. It links HFSC-intrinsic and developmentally regulated programs with the need for environment sensing – emphasizing the importance of the niche surrounding HFSCs in regulating stem cell activity. After reading this paper, I like to hypothesize that the cyclical fluctuations of Tlr2 expression in HFSCs might be driven through dynamic changes in the immune landscape around the hair follicle. HFSCs so far have been believed to reside in an immune-privileged niche and to interact with rather few immune cells. However, a comprehensive and unbiased analysis of the hair follicle immune landscape across hair cycle stages is still missing – and appears to become increasingly intriguing.
Posted on: 14 September 2023 , updated on: 15 September 2023
doi: https://doi.org/10.1242/prelights.35569
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