# Vitamin D Merging into Immune System-Skeletal Muscle Network: Effects on Human Health
## 2 Vitamin D Coordinates the Anti-Inflammatory Immune Response  
VDR agonists are known since quite ago as fine-tuned modulators of the immune system. VDR is present in the majority of immune cell types: T cells, including CD4+ and CD8+ subtypes, B cells, neutrophils, and antigen-presenting cells (APCs), as macrophages and dendritic cells (DCs) [23], and it is expressed at different levels, according to the physiological phase and immune signal modulation. During the T cell activation, i.e., a broad VDR upregulation occurs, while the receptor is expressed at very low levels in naive T cells. Conversely, a significant VDR downregulation associates with macrophages or DCs maturation from monocytes [24; 25; 26; 27]. It is well known that vitamin D actively participates to innate immune response building by promoting macrophage chemotactic and phagocytic activity. This hormone can finely drive immune-adaptive responses as well, by targeting APCs, mainly DCs. Indeed, it counteracts DCs maturation/differentiation from monocytes, inhibits the expression of both costtimulatory molecules and the major histocompatibility complex (MHC)-II-complexed antigen on the DC surface, consequently impairing antigen processing and presentation to T cells [28]. In addition, vitamin D directly polarizes T cell-responses from T helper (Th)1/Th17 inflammatory phenotypes to the Th2 tolerogenic subset. Notably, many effects of vitamin D on immune response polarization are driven by a straight inhibition of pro-inflammatory Th1/Th17 type cytokines, such as interleukin (IL)-2, IL-6, IL-23, IL-1, IL-8, IL-12, interferon (IFN)\(\gamma\), and tumor necrosis factor (TNF)\(\alpha\), IL-17, and IL-21; meanwhile, protolerogenic Th2 cytokine subset production, i.e., IL-10 and IL-4 is simultaneously enhanced [18; 29; 30; 31; 32; 33]. The concurrent downregulation of inflammatory cytokines and the upregulation of protolerogenic cytokines or neutraligands, as IL-10 and CCL22, with anti-inflammatory activity, allows T regulatory (Treg) cell expansion [30; 32; 33]. Furthermore, VDR agonists impair the inflammatory cascade in macrophages by targeting cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), leading, in turn, to a significant reduction in nitric oxide (NO) and prostaglandin (PG)E2 content [29]. Vitamin D can suppress plasma-cell differentiation, B cell proliferation/differentiation, and antibody (IgG and IgM) production as well [34; 35]. Importantly, DCs, macrophages, T cells, and B cells are able to synthesize vitamin D, which, in turn, downregulates the local expression of IL-12 and IL-23 and costtimulatory molecules (i.e., CD40, CD80, CD86); therefore, modulating the immune response within the infiltrated target tissues as well [18; 34]. Hence, an adequate level of vitamin D warrants a correct function of the immune response, promotes protolerogenic immune dominance, and protects from chronic inflammation, as shown in Figure 1.  
At variance, vitamin D insufficiency/deficiency is shown to promote altered immune response and inflammation, which is shown to be associated with the development and maintenance of several pathologic conditions.