Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti-Inflammatory

Abstract

Regulation of immune function continues to be one of the most well-recognized extraskeletal actions of vitamin D. This stemmed initially from the discovery that antigen presenting cells such as macrophages could actively metabolize precursor 25-hydroxyvitamin D (25D) to active 1,25-dihydroxyvitamin D (1,25D). Parallel observation that activated cells from the immune system expressed the intracellular vitamin D receptor (VDR) for 1,25D suggested a potential role for vitamin D as a localized endogenous modulator of immune function. Subsequent studies have expanded our understanding of how vitamin D exerts effects on both the innate and adaptive arms of the immune system. At an innate level, intracrine synthesis of 1,25D by macrophages and dendritic cells stimulates expression of antimicrobial proteins such as cathelicidin, as well as lowering intracellular iron concentrations via suppression of hepcidin. By potently enhancing autophagy, 1,25D may also play an important role in combatting intracellular pathogens such as M. tuberculosis and viral infections. Local synthesis of 1,25D by macrophages and dendritic cells also appears to play a pivotal role in mediating T-cell responses to vitamin D, leading to suppression of inflammatory T helper (Th)1 and Th17 cells, and concomitant induction of immunotolerogenic T-regulatory responses. The aim of this review is to provide an update on our current understanding of these prominent immune actions of vitamin D, as well as highlighting new, less well-recognized immune effects of vitamin D. The review also aims to place this mechanistic basis for the link between vitamin D and immunity with studies in vivo that have explored a role for vitamin D supplementation as a strategy for improved immune health. This has gained prominence in recent months with the global coronavirus disease 2019 health crisis and highlights important new objectives for future studies of vitamin D and immune function. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Keywords: ANTIBACTERIAL; AUTOPHAGY; CATHELICIDIN; HEPCIDIN; INFLAMMATION; NOD2; Th1; Th17; Treg; VITAMIN D; β‐DEFENSIN 2.

Fig 1

Vitamin D metabolism and innate immune signaling in the monocyte/macrophage. Schematic representation illustrating the regulation of expression of genes that encode antimicrobial peptides, pattern recognition receptors, and cytokines/chemokines by the 1,25D‐bound vitamin D receptor (VDR). In response to 1,25D, the VDR induces expression of the pattern recognition receptor NOD2, antimicrobial peptides CAMP and HBD2/DEFB4, and cytokines IL‐1β and IL‐8. The 1,25D‐VDR complex also functions to suppress HAMP expression, leading to increased ferroportin‐mediated export of iron. Upon stimulation with the ligand muramyl dipeptide (MDP) generated by the breakdown of bacterial peptidoglycan, NOD2 and IL‐1β can enhance HBD2, CAMP, and IL1B expression.

Fig 2

Immunomodulatory effects of 1,25D on CD4⁺ T cells. T‐cell‐receptor signaling induces an upregulation in the vitamin D receptor (VDR), which is stabilized from degradation by 1,25D binding. IL‐2 production is suppressed by 1,25D signaling after T‐cell activation. Th1‐ and Th17‐cell differentiation is suppressed by vitamin D₃ signaling along with characteristic, inflammatory cytokine production. CCR6 on Th17 cells is also suppressed, preventing homing to tissues. Downregulation of transcription factors T‐bet and RORγt is less consistently reported. Th2‐cell differentiation is widely thought to be increased by 1,25D, although this is dependent on conditions. 1,25D causes upregulation of IL‐4 and STAT‐6, which increases GATA‐3. Overall, the Th1/Th2 balance is in the favor of Th2 cells. Similarly, the Th17/iTreg balance favors Tregs with the addition that Th17 cells, additionally suppressed by FoxP3 upregulation, can convert to a Treg phenotype. 1,25D upregulates IL‐10, TGF‐β, and inhibitory markers CTLA‐4 and CD25 to promote an anti‐inflammatory phenotype.