Hypothalamic-pituitary-derived melanocortin axis links to myelopoiesis and immunotherapy

Graphic abstract of hypothalamic-pituitary-bone marrow (HPB) axis

Melanocortins, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropin (ACTH), are ancient peptides highly conserved in vertebrates and exhibit diverse well-established functions, including dermal pigmentation, adrenal steroidogenesis and cell proliferation, energy homeostasis, and inflammation.1 Melanocortins exert their diverse functions through five melanocortin receptors (MCRs), MC1R–MC5R, numbered based on the sequence of their cloning. A PubMed search performed on May 22, 2023, using MC1R, MC2R, MC3R, MC4R, and MC5R as the search term retrieved 1,815, 474, 554, 2270, and 252 entries, suggesting that compared with the other four MCRs, MC5R received less attention.

Originally identified as a major player for lipid production in the sebaceous and preputial glands in 1997, additional sites of expression and physiological functions of MC5R signaling such as stress response, thermoregulation, and lipid metabolism have been elucidated. MC5R also participates in regulating immune homeostasis in the adipocytes, airway epithelial cells, ocular Treg cells, and spleen antigen-presenting cells.