New research has discovered hemoglobin in the uppermost layer of human skin for the first time and found that it helps protect the skin from damage. These findings provide important insights into aging and skin diseases such as cancer. Hemoglobin is known to bind oxygen in the blood and carry it from the lungs to the tissues. However, a new study finds that hemoglobin has another role: protecting our skin from damage.
Researchers were interested in understanding how the epidermis - the outermost layer of skin - protects us from environmental challenges such as UV rays, so they looked at what's going on in the skin at the molecular level.
Masayuki Amagai, the corresponding author of the study, said: "The epidermis is composed of keratinized stratified squamous epithelium, mainly composed of keratinocytes. Previous studies have found that during the process of keratinocyte differentiation and formation of the skin's outer barrier, they express a variety of genes with protective functions. However, due to the difficulty in obtaining sufficient numbers of isolated terminally differentiated keratinocytes for transcriptome analysis, other barrier-related genes escaped previous protection."
Epidermal keratinocytes originate from the deepest layer of the skin (the basal layer) and move upward to form several layers after differentiation. During the differentiation stage of keratinocytes, the expression of various genes with protective barrier functions has been discovered, and diseases such as atopic dermatitis are caused by genetic mutations.
To identify unknown molecules involved in skin barrier mechanisms, the researchers analyzed highly expressed genes in the entire epidermis and upper epidermis of healthy human skin taken from the thighs and upper arms of three individuals, as well as in mouse skin. They unexpectedly discovered that the HBA1/2 genes encoding alpha-globulin, one of the protein subunits of hemoglobin, are highly expressed in the upper epidermis of human skin. Similarly, in mouse skin, Hba-a1/a2 (equivalent to human HBA1/2) are also highly expressed in the upper epidermis.
"We performed a comparative transcriptome analysis of the whole epidermis and the upper epidermis, which are sheets of cells isolated from human and mouse skin using enzymes," said Amagai. "We found that the genes responsible for producing hemoglobin are highly active in the upper epidermis. To confirm this finding, we used immunostaining to look at the presence of hemoglobin alpha protein in keratinocytes in the upper epidermis."
Researchers irradiated skin with UVA and UVB separately and found that UVA (but not UVB) could induce the expression of HBA1/2 in epidermal keratinocytes. UVA irradiation is the main cause of reactive oxygen species (ROS)-mediated keratinocyte damage. Compared with the control group, the intracellular ROS levels of HBA knockout keratinocytes were significantly increased, indicating that the expression of HBA is induced to inhibit UVA-induced ROS generation in epidermal keratinocytes.
Mitochondria - the energy producers of cells - are particularly sensitive to excess ROS produced by UV radiation, and mitochondrial dysfunction caused by UV radiation directly leads to skin damage, also known as photoaging.
"Our study shows that epidermal hemoglobin is upregulated under oxidative stress and inhibits the production of reactive oxygen species in human keratinocyte cultures," Amagai said. "Our results show that hemoglobin alpha protects keratinocytes from external or internal oxidative stress, such as ultraviolet radiation and impaired mitochondrial function. Therefore, hemoglobin expression by keratinocytes represents an endogenous defense mechanism against skin aging and skin cancer."
The researchers say their findings provide important implications for studying ROS-related skin diseases, such as aging and cancer.
The study was published in the Journal of Investigative Dermatology.