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          Spotlight on Research
          Researchers identify cellular pathway that regulates inflammatory hair loss





Spotlight on Research


Researchers identify cellular pathway that regulates inflammatory hair loss Stephanie Mathews, Ph.D. | *December 13, 2021*
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              Photo of Dr. NagaoOverview

Hair can grow from most areas of our body, from the head to the top of our feet. Hair helps keep us warm, but it also plays a role in another important biological function—protecting our bodies from harmful pathogens. In a paper published October 12, 2021, in *Immunity*, NIH researchers reveal new insights about the relationship between hair and hair follicles and the skin’s immune system.

Hair grows from structures called hair follicles found all over our skin. Hair follicles are home to immune cells and beneficial bacteria. Working together, these immune cells and bacterial cells help regulate skin immunity.

For hair follicles to help keep skin healthy, they must maintain a proper balance among their resident bacteria. The NIH researchers identified a biological pathway that plays a key role in maintaining this balance. The scientists showed that if this signaling pathway, known as ADAM10-Notch, is disrupted, the balance of bacteria in the skin is altered. This bacterial imbalance caused an inflammatory response that destroyed hair follicles and resulted in irreversible hair loss.

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To study the role of ADAM10 in skin immunity, researchers engineered mice in which the ADAM10 gene could be turned off in hair follicles. To turn off the gene, scientists injected the mice with a substance that mimics viral infection and activates an immune response. The scientists isolated hair follicle cells from all the ADAM10-deficient mice (and some control mice with unaltered ADAM10) and used sequencing techniques to analyze gene expression in the cells.
	ADAM10 exerts its effects by activating a protein called Notch. Compared to control mice, mice lacking ADAM10 showed increased expression of inflammatory response genes, decreased anti-inflammatory gene expression, and decreased Notch signaling. These results demonstrated that ADAM10-Notch signaling helps control the inflammatory response in hair follicles.
	The scientists observed hair loss in ADAM10-deficient mice. These mice also had higher than normal levels of immune cells called innate lymphoid cells (ILCs). The ILCs triggered inflammation that destroyed hair follicles, leading to hair loss. The inflammatory destruction of hair follicles seen in ADAM10-deficient mice mimics a type of permanent hair loss called cicatricial alopecia, a rare disorder in which hair follicles are replaced with scar tissue.
	*Corynebacterium* species, which are bacteria normally found on the skin in low quantities, were significantly more abundant in the hair follicles and skin of ADAM10-deficient mice. This observation suggested that lack of ADAM10 led to an imbalance in resident bacteria.
	The scientists administered oral and topical antibiotics to the mice to block accumulation of excess *Corynebacterium*. The treatment prevented hair loss, stopped the accumulation of ILCs in hair follicles, and prevented an inflammatory response. These results suggested that imbalance of resident bacteria drove inflammatory hair loss.
	Researchers studied mice with impaired Notch signaling to better understand the role of the ADAM10-Notch pathway in inflammatory hair loss. Like ADAM10-deficient mice, mice with impaired Notch signaling exhibited hair loss and increased *Corynebacterium* levels that antibiotic treatment could reverse.
	This work identified the critical role of ADAM10-Notch signaling in regulating the balance of resident bacteria in hair follicles to prevent inflammatory hair loss.NIH researchers from NIAMS and the National Human Genome Research Institute contributed to this study.

“Our findings reveal that the relationships between host and bacteria in hair follicles are mediated by the ADAM10-Notch signaling pathway. Disruption of this pathway leads to inflammatory destruction of hair follicles, leading to irreversible hair loss that is reminiscent of cicatricial (scarring) alopecia in humans.” Keisuke (Chris) Nagao, M.D., Ph.D., senior study author, Head and Senior Investigator, Cutaneous Leukocyte Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

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Disruption of the endopeptidase ADAM10-Notch signaling axis leads to skin dysbiosis and innate lymphoid cell-mediated hair follicle destruction. Sakamoto K, Jin SP, Goel S, Jo JH, Voisin B, Kim D, Nadella V, Liang H, Kobayashi T, Huang X, Deming C, Horiuchi K, Segre JA, Kong HH, Nagao K. *Immunity*. 2021 Oct 12;54(10):2321-2337.e10. doi: 10.1016/j.immuni.2021.09.001. Epub 2021 Sep 27. PMID: 34582748. 
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