Legend has it that fright, stress, or grief may drain the color from one’s hair overnight. Nothing quite like this phenomenon has been confirmed by science, though gradual hair graying has been studied to uncover mechanisms of stem cell self-renewal. For example, hair graying in mice has been associated with the premature differentiation of melanocyte stem cells (McSCs) and their eventual depletion. Now, in a new study from researchers at the National Institutes of Health (NIH) and the University of Alabama, hair graying has also been associated with dysregulation of the innate immune system.

Both hair-graying associations—premature McSC differentiation and immune dysregulation—have a common link—the melanogenesis associated transcription factor, or MITF. This transcription factor, it turns out, does double duty. It affects both the genes that affect hair color and the genes that notify our body of a pathogenic infection.

When a body is under attack from a virus or bacteria, the innate immune system kicks into gear. All cells can detect foreign invaders, and they respond by producing signaling molecules called interferons. Interferons signal to other cells to act by turning on the expression of genes that inhibit viral replication, activate immune effector cells, and increase host defenses.

In melanocytes, the researchers found, the interferon response is kept in check by MITF, which is far better known for its role in regulating the many functions within melanocytes. Also, the researchers determined that if MITF's control of the interferon response is lost in melanocyte stem cells, hair graying results. Furthermore, if innate immune signaling is artificially activated in mice that are predisposed for getting gray hair, increased numbers of gray hairs are also produced.

These findings appeared May 3 in the journal PLOS Biology, in an article entitled “A Direct Link between MITF, Innate Immunity, and Hair Graying.”

“Based on transcriptome and molecular analyses of Mitfmi-vga9/+ mice, we report a novel role for MITF in the regulation of systemic innate immune gene expression,” wrote the article’s authors. “We also demonstrate that the viral mimic poly(I:C) is sufficient to expose genetic susceptibility to hair graying.”

The connection between hair pigmentation and innate immune regulation was initially a bit surprising. “Genomic tools allow us to assess how all of the genes within our genome change their expression under different conditions, and sometimes they change in ways that we don't anticipate,” explained Melissa Harris, Ph.D., primary author and assistant professor of biology at UAB. “We are interested in genes that affect how our stem cells are maintained over time. We like to study gray hair because it's an easy readout of melanocyte stem cell dysfunction.”

“This new discovery suggests that genes that control pigment in hair and skin also work to control the innate immune system,” added William Pavan, Ph.D., study co-author and chief of the Genetic Disease Research Branch at NIH's National Human Genome Research Institute (NHGRI). “These results may enhance our understanding of hair graying. More importantly, discovering this connection will help us understand pigmentation diseases with innate immune system involvement like vitiligo.” Vitiligo, which causes discolored skin patches, affects 0.5% to 1% of all humans.

Why mice that are predisposed for getting gray hair are more susceptible to dysregulated innate immune signaling remains to be answered. The researchers speculate that perhaps this can explain why some people experience premature gray hair early in life, and they will continue their studies to address this question.

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