Abstract
In this Review article, we focus on delineating the expression and function of Peptidyl Arginine Delminases (PADIs) in the hair follicle stem cell lineage and in inflammatory alopecia. We outline our current understanding of cellular processes influenced by protein citrullination, the PADI mediated posttranslational enzymatic conversion of arginine to citrulline, by exploring citrullinomes from normal and inflamed tissues. Drawing from other stem cell lineages, we detail the potential function of PADIs and specific citrullinated protein residues in hair follicle stem cell activation, lineage specification and differentiation. We highlight PADI3 as a mediator of hair shaft differentiation and display why mutations in PADI3 are linked to human alopecia. Furthermore, we propose mechanisms of PADI4 dependent fine-tuning of the hair follicle lineage progression. Finally, we discuss citrullination in the context of inflammatory alopecia. We present how infiltrating neutrophils establish a citrullination-driven self-perpetuating proinflammatory circuitry resulting in T-cell recruitment and activation contributing to hair follicle degeneration. In summary, we aim to provide a comprehensive perspective on how citrullination modulates hair follicle regeneration and contributes to inflammatory alopecia.
Highlights
Hair follicles (HFs) undergo phases of destruction and regeneration throughout the lifespan of an organism
We focus on how citrullination contributes to hair follicle lineage progression during regeneration, and how citrullination-mediated inflammation acts to perpetuate disease progression in inflammatory alopecia
It is interesting that the biological processes linked to citrullination are distinct in normal and inflamed tissue, hinting at key cellular functions where citrullination is required for maintaining cell identity in non-inflamed tissue, as well as identifying aspects of citrullination-dependent biology which could be explored for therapeutic purposes during inflammation
Summary
Hair follicles (HFs) undergo phases of destruction and regeneration throughout the lifespan of an organism. Regeneration and hair formation depend on balanced stem cell renewal and differentiation, integrating transcriptional and epigenetic regulation with microenvironmental niche-derived cues. Respond to inflammatory signals, deregulates hair follicle lineage progression, abrogates regeneration, and commonly leads to alopecia. Whereas our understanding of how posttranslational modifications affects stem cell lineage progression and disease progression is far from complete, extensive work identifying histone modification “codes” acting to maintain cell states as well as to ensure proper lineage progression, suggest that the impact of protein modifications requires further investigation. We focus on how citrullination contributes to hair follicle lineage progression during regeneration, and how citrullination-mediated inflammation acts to perpetuate disease progression in inflammatory alopecia. We hope that this work will inspire scientists to explore new citrullination paved avenues towards the understanding of skin and skin disease
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