Human Perifollicular Macrophages Undergo Apoptosis, Express Wnt Ligands, and Switch their Polarization during Catagen

Hardman, Jonathan A.; Muneeb, Ferhan; Pople, Jenny; Bhogal, Ranjit; Shahmalak, Asim; Paus, Ralf

doi:10.1016/j.jid.2019.04.026

Cited by 30 publications

(26 citation statements)

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“…Additionally, qPCR results of upregulated mRNA levels of transcription factors (Axin2 and Lef1) further confirmed the function of translocated β-catenin in DP cells, by activating transcription factors important for anagen induction and maintenance. Our results are in agreement with a recent study, which showed that macrophages present near the hair follicles are positive for Wnt proteins, and also showed secreted Wnt10a near the DP cell and activates axin2 and Lef1 [21]. This study proved that Wnt3a/Wnt7b associated with MAC-EVs induced hair growth by activating receptors and relayed β-catenin cascade in DP cells.…”

Section: Discussionsupporting

confidence: 93%

“…Another study showed that macrophages induce HF growth through tumor necrosis factor (TNF)-induced AKT/β-catenin signaling in Leucine-rich G-protein-coupled receptor 5 (Lgr5) + HF stem cells [20]. A recent study clearly showed that human perifollicular macrophages maintain the anagen stage in humans by activating DP cells by secreting Wnt proteins [21]. However, the effect of macrophage-derived EVs (MAC-EVs) on the activation of dermal papilla (DP) cells and hair growth is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Macrophage-Derived Extracellular Vesicle Promotes Hair Growth

Rajendran

Gangadaran

Seo

et al. 2020

Cells

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Hair loss is a common medical problem affecting both males and females. Dermal papilla (DP) cells are the ultimate reservoir of cells with the potential of hair regeneration in hair loss patients. Here, we analyzed the role of macrophage-derived Wnts (3a and 7b) and macrophage extracellular vesicles (MAC-EVs) in promoting hair growth. We studied the proliferation, migration, and expression of growth factors of human-DP cells in the presence or absence of MAC-EVs. Additionally, we tested the effect of MAC-EV treatment on hair growth in a mouse model and human hair follicles. Data from western blot and flow cytometry showed that MAC-EVs were enriched with Wnt3a and Wnt7b, and more than 95% were associated with their membrane. The results suggest that Wnt proteins in MAC-EVs activate the Wnt/β-catenin signaling pathways, which leads to activation of transcription factors (Axin2 and Lef1). The MAC-EVs significantly enhanced the proliferation, migration, and levels of hair-inductive markers of DP cells. Additionally, MAC-EVs phosphorylated AKT and increased the levels of the survival protein Bcl-2. The DP cells treated with MAC-EVs showed increased expression of vascular endothelial growth factor (VEGF) and keratinocyte growth factor (KGF). Treatment of Balb/c mice with MAC-EVs promoted hair follicle (HF) growth in vivo and also increased hair shaft size in a short period in human HFs. Our findings suggest that MAC-EV treatment could be clinically used as a promising novel anagen inducer in the treatment of hair loss.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Macrophage-Derived Extracellular Vesicle Promotes Hair Growth

Rajendran

Gangadaran

Seo

et al. 2020

Cells

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“…For example, mouse skin with all HFs in mid‐late anagen exhibits a profoundly immunoinhibitory milieu, 53,54 most likely due to the secretion of immunoinhibitory IP guardians by HFs. Further, the number, phenotype, apoptosis‐modulating activities and protein expression patterns of perifollicular macrophages significantly fluctuate during the human anagen‐catagen switch, 55 similar to observations in mice. 56 While it is as yet unclear what exactly this means for HF IP, it suggests that HF cycling can alter the local immune status of skin.…”

Section: The Biological Function Of Hair Follicle Immune Privilegesupporting

confidence: 73%

Hair follicle immune privilege and its collapse in alopecia areata

Bertolini

McElwee

Gilhar

et al. 2020

Experimental Dermatology

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Anagen stage hair follicles (HFs) exhibit “immune privilege (IP)” from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra‐follicular antigen presentation via MHC class I and II molecules, along with prominent expression of “no danger” signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. Perifollicular mast cells, Tregs and other immunocytes may also contribute to HF IP maintenance in healthy human skin. Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro‐inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T‐cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T‐cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. While IP collapse may be induced by exogenous agents, inherent IP deficiencies might confer increased susceptibility to AA for some individuals. Thus, a key goal for effective AA management is the re‐establishment of a functional HF IP, which will also provide superior protection from disease relapse.

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“…Currently, most of our understanding of the immune infiltrate during the human hair cycle is descriptive and confined to mostly anagen HFs, which is the predominant phase found in human scalps. Ex vivo analysis of human HFs is limited to anagen and catagen follicles, and telogen hairs are difficult to dissect and maintain in culture. Functional studies done in mice and small mammals have been extrapolated to human HF biology in order to develop new treatments, but actual mechanistic studies in humans are lacking.…”

Section: Discussionmentioning

confidence: 99%

Immune cell regulation of the hair cycle

Wang

2020

Experimental Dermatology

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The ability to manipulate the mammalian hair cycle will lead to novel therapies and strategies to combat all forms of alopecia. Thus, in addition to the epithelial‐mesenchymal interactions in the hair follicle, niche and microenvironmental signals that accompany the phases of growth, regression and rest need to be scrutinized. Immune cells are well described in skin homeostasis and wound healing and have recently been shown to play an important role in the mammalian hair cycle. In this review, we will summarize our current knowledge of the role of immune cells in hair cycle control and discuss their relevance to human hair cycling disorders. Increased attention to this aspect of the hair cycle will provide new avenues to manipulate hair regeneration in humans and provide better insight into developing better ex vivo models of hair growth.

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Human Perifollicular Macrophages Undergo Apoptosis, Express Wnt Ligands, and Switch their Polarization during Catagen

Abstract: We would like to thank R Marotta/IIT for support with IM-TEM and acknowledge Kim Mace for reviewing the manuscript. This work was supported by grants from Unilever, UK, and the NIHR Manchester BRC (BRC-1215-20007) "Inflammatory Hair Diseases" program.

Cited by 30 publications

References 50 publications

Macrophage-Derived Extracellular Vesicle Promotes Hair Growth

Macrophage-Derived Extracellular Vesicle Promotes Hair Growth

Hair follicle immune privilege and its collapse in alopecia areata

Immune cell regulation of the hair cycle

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