NIAID-supported investigators have found that vitamin D and parathyroid hormone (PTH), which regulates calcium metabolism and bone health, work together to enhance immune defenses in the skin. These observations, obtained from mouse models and cultured human skin cells, are the first to suggest a protective role for PTH and imply a possible new approach to treat bacterial, fungal and viral skin infections, which are particularly common in patients with atopic dermatitis, a type of eczema.
People with atopic dermatitis experience dry, itchy skin rashes that can swell, crack, or weep fluid. They also are more susceptible to some bacterial and viral skin infections because their skin cells make fewer antimicrobial peptides (AMPs), molecules that help to prevent the invasion of harmful microbes.
One such AMP is cathelicidin. Low production of cathelicidin by skin cells has been associated with a high risk of infections caused by certain viruses, as well as Group A Streptococcus bacteria and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA).
Many laboratory studies have demonstrated a role for vitamin D in the production of AMPs. However, only a few clinical trials have shown either that adding vitamin D supplements to the diet provides protection against harmful bacteria or that people with low vitamin D have higher rates of infections.
These conflicting observations led investigators in the NIAID-supported Atopic Dermatitis Research Network (ADRN) to explore what other factors may be involved in protecting the skin from bacterial infections.
The ADRN research team, led by Richard Gallo, M.D., Ph.D., at the University of California San Diego, found that PTH played an unexpected and vital role.
In a series of experiments in cultured human skin cells, the investigators showed that the presence of microbial products induced the production of PTH and its receptor, which in turn induced the production of cathelicidin. Further experiments found that this process required the cooperation of active vitamin D.
To see if the PTH-vitamin D interaction conferred protection in a living organism, the investigators turned to a mouse model. They administered PTH to mice that were on a normal diet containing vitamin D, and infected them with Group A Streptococcus 24 hours later. Normal (wild-type) mice given PTH had fewer bacteria in their skin and smaller lesion size, compared to mice that were not given PTH. However, knockout mice that were made unable to convert dietary vitamin D into active vitamin D were not protected when given PTH.
Because vitamin D appears to play a critical role in protecting people from infections, the research team wanted to know why low dietary vitamin D does not correspond with greater susceptibility to infections. The team fed one group of wild-type mice a normal diet and another group of wild-type mice a diet low in vitamin D. When they attempted to induce a Group A Streptococcus infection, the vitamin D-deficient mice were no more susceptible to bacterial infection than mice on a normal diet.
Examining the blood of the vitamin D-deficient mice revealed that PTH levels increased to compensate for low vitamin D. Cathelicidin expression in the skin therefore increased in response to Group A Streptococcus challenge, regardless of the diet the mice received.
However, knockout mice that were given a diet low in vitamin D were shown to be more susceptible to bacterial infection, when compared to knockout mice on a normal diet. Because PTH-vitamin D interaction is disrupted in the knockout mice, PTH did not increase in response to low dietary vitamin D; therefore, cathelicidin expression in these mice did not increase in response to infection.
Although cooperation between the hormone PTH and vitamin D is well established, this interaction has largely been attributed to regulating calcium in the blood. Findings by the ADRN team suggest that PTH and vitamin D act together to induce the expression of cathelicidin, revealing a protective role for PTH in the skin.
Because experiments performed in cultured human skin cells and mouse models indicate a direct correlation between PTH and vitamin D concentrations and production of cathelicidin, it is possible that PTH might eventually be used to treat bacterial, fungal and viral skin infections. This will be especially important for patients with atopic dermatitis, who have low levels of cathelicidin.
More research is needed to understand how PTH and vitamin D stimulate AMP production. Current ADRN studies are underway to examine the activity of PTH in people who are healthy and those with atopic dermatitis.
Muehleisen B, Bikle DD, Aguilera C, Burton DW, Sen G, Deftos LJ, Gallo RL. PTH/PTHrP and vitamin D control antimicrobial peptide expression and susceptibility to bacterial skin infection. Science Translational Medicine. 2012 May 23 [Epub ahead of print].
View NIAID information on eczema.
Last Updated June 08, 2012
Last Reviewed June 08, 2012