An implication for post-transcriptional control: reciprocal changes of melanocortin receptor type 2 mRNA and protein expression in alopecia areata

Alopecia areata (AA) is a hair follicle-specific autoimmune disease that is inherited genetically but triggered environmentally. Stress response is believed to play a role in the pathogenesis of AA. The hypothalamic-pituitary-adrenal axis (HPA axis), known as the stress axis, plays a cardinal role in the stress response. Growing evidence demonstrates that stress responses are under the control of both the central and peripheral nervous systems. Skin and hair follicles display peripheral HPA axis-like signaling systems. Some studies have revealed that a modified HPA axis, which is characterized by enhanced CRH/CRHR and insufficient glucocorticoid, is involved in the pathology of AA, suggesting that the paradoxical expression differs from that of normal control and should be further examined. Because adrenocorticotropic hormone (ACTH) is an intermediary in the HPA axis, MC2R, which specifically binds ACTH, may be important in the stress response of skin. Therefore, we investigated the gene and protein expression of MC2R in AA lesions and tried to elucidate the connection between HPA axis regulation, MC2R and AA. Reciprocal changes in MC2R mRNA and proteins in human AA were observed in our study; while mRNA levels were higher in lesions from AA patients compared with scalp tissues from normal controls, protein levels of MC2R were lower. The paradoxical expression of MC2R gene and protein levels coincided with evidence that over-responsive HPA activity coexists with a deficient HPA response in AA. We hypothesized that the HPA axis response in human AA may be the following: stressors first activate excess CRH/CRHR to produce increased ACTH, which up-regulates the expression of MC2R mRNA, but the stress response cannot create sufficient cortisol when the binding of ACTH/MC2R is deficient due to decreased MC2R protein. This hypothesis rationally clarifies the changed HPA axis in human AA and highlights the importance of MC2R in the pathogenesis of AA. The inconsistent expression of protein and mRNA implicates post-transcriptional control of human MC2R gene expression as found in murine MC2R gene.