# Vitamin D Merging into Immune System-Skeletal Muscle Network: Effects on Human Health
## 5 Myokines, Immune Regulation, and Vitamin D: Converging Cell Signaling  
Remarkably, upon contraction, the skeletal muscle releases a plethora of regulatory factors, named myokines, which are increasingly recognized to exert a fine-tuned control on biological age and health status, and are even proposed as frailty biomarkers [73]. To date, the proteomic profiling of the skeletal muscle secretome identified more than 300 myokines, potentially able to control nearby or distant organ function in autocrine, paracrine, and endocrine fashion [72; 74; 75]. Out of all, some myokines, such as IL-6, IL-7, IL-15 seem to actively control and support immune system function [61]. IL-15-dependent signaling is engaged in human neutrophil migration and phagocytosis control, naive T-cells survival, macrophage differentiation, and B cell proliferation [76]. Importantly, IL-15 helps the clearance of viral pathogens and tumor cells by promoting the proliferation and activation of NK cells and CD8+T cell homeostasis [77]. Accordingly, IL-15 knockout mice showed a defective immune response to viral vaccinia [78]. During skeletal muscle function deterioration, i.e., consequent to aging, diseases, or inactivity, a significant IL-15 decline is found in association with the immune defense decline and higher risk of infection [79]. IL-15 plays a pivotal role in macrophage differentiation--the cytokine itself can induce a cascade from alpha hydroxylase CYP27b1 activation necessary for [25(OH)D] conversion into bioactive [1,25(OH)\({}_{2}\)D], ending in VDR activation and the induction of cathelicidin, an antimicrobial peptide largely engaged in first-line host defense [80; 81]. A competent VDR is unquestionably required to mount a suitable immune response to intracellular pathogens [82]; the addition of vitamin D during IL-15-induced differentiation of monocytes into macrophages dose-dependently increased cathelicidin [83; 84]. Interestingly, as from studies performed in human placental trophoblasts, a sex-dependent dimorphism in vitamin D metabolism would explain the major immune vulnerability to perinatal infections found in male fetuses and neonates vs. female ones. In fact, testosterone seems to decrease cathelicidin gene expression through CYP27B1 inhibition [85], thus impairing male immune defense. It would be very interesting to ensure further research in post-natal and adult life to investigate whether this mechanism might explain some sex-dependent differences (too often neglected) observed in response to infections [86], including the pandemic from the novel coronavirus disease 2019 (COVID-19) present at time of writing this text, which is reported to affect prevalently men [87]. IL-7, mostly produced in the thymus, is expressed and secreted by human skeletal muscle cells as well; it is classified as an exercise-regulated myokine, and exercise can restore IL-7 decline induced by aging [79; 88]. IL-7-dependent signaling is critical for thymic development and function and thymic/extrathymic lymphocyte development and maturation (in particular, \(\gamma\delta\) T cells), necessary in maintaining immune competence, particularly, in first-line immune defense [89]. Lower circulating IL-7 is reported in conditions of impaired lymphopoiesis, as occurs in elderly humans or in subjects positive for human immunodeficiency virus (HIV) [90; 91; 92; 93; 94]. Studies on animals and humans include IL-7/vitamin D combination among the strategies to fight age-related immunosenescence, vulnerability to infections, and susceptibility to inflammatory diseases [95; 96]. Furthermore, dysregulation of IL-7 signaling seems to be engaged in several autoimmune inflammatory processes [97]. In this context, vitamin D supplementation has been hypothesized as a tool to prevent autoimmune reactions by targeting and reducing IL-7 defective signaling [98]. Concerning IL-6, this is primarily known as a cytokine underlying inflammation-related diseases, including insulin resistance (IR) development [99; 100].