Cell‐type‐specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes

Abstract

SummaryVitamin D is widely reported to inhibit innate immune signalling and dendritic cell (DC) maturation as a potential immunoregulatory mechanism. It is not known whether vitamin D has global or gene-specific effects on transcriptional responses downstream of innate immune stimulation, or whether vitamin D inhibition of innate immune signalling is common to different cells. We confirmed vitamin D inhibition of nuclear factor-jB (NF-jB) and p38 mitogen-activated protein kinase (MAPK) signalling in monocyte-derived DC (MDDC) stimulated with lipopolysaccharide (LPS). This was associated with global but modest attenuation of LPS-induced transcriptional changes at genome-wide level. Surprisingly, vitamin D did not inhibit innate immune NF-jB activation in monocytederived macrophages. Consistent with our findings in MDDC, ex vivo vitamin D treatment of primary peripheral blood myeloid DC also led to significant inhibition of LPS-inducible NF-jB activation. Unexpectedly, in the same samples, vitamin D enhanced activation of both NF-jB and MAPK signalling in primary peripheral blood monocytes. In a cross-sectional clinical cohort, we found no relationship between peripheral blood vitamin D levels and LPS-inducible activation of NF-jB and MAPK pathways in monocytes of myeloid DC. Remarkably, however, in vivo supplementation of people with vitamin D deficiency in this clinical cohort also enhanced LPS-inducible MAPK signalling in peripheral blood monocytes. Therefore, we report that vitamin D differentially modulates the molecular response to innate immune stimulation in monocytes, macrophages and dendritic cells. These results are of importance in the design of studies on vitamin D supplementation in infectious and immunological diseases.

The Role of Vitamin D in the Immune System as a Pro-survival Molecule

“…[110][111][112] Conversely, in monocytes/macrophages, the expression of 1α-hydroxylases is regulated by IFN-γ and the CD14/TLR4 interaction, in a synergistic way, due to the molecular action of C/EPB-β, Clinical Therapeutics following the activation of signaling pathways involving p38MAPK, JAK/STAT, and NF-κB. 113 At least as observed in animal models, vitamin D (mainly through its VDR) exerts a fundamental role on macrophage activity and polarization, particularly in their ability to respond to injury causing an inflammatory reaction.…”

Vitamin D Compounds Are Bactericidal against Streptococcus mutans and Target the Bacitracin-Associated Efflux System

“…In addition to contributing to overall well-being, many reports examining the relationship between vitamin D and infection focus on the direct, significant immunomodulatory role of vitamin D (reviewed in reference 29). Vitamin D alters the innate immune response (30), and in turn, immune cells differentially regulate vitamin D-metabolizing enzymes during infection (31). One mechanism for this is stimulation by vitamin D of the production of antimicrobial peptides, such as cathelicidin and human ␤-defensin 2, as well as stimulation of cell-specific receptors involved in pathogen clearance (32)(33)(34).…”

Prominent Levels of the Profibrotic Chemokine CCL18 during Peritonitis:In VitroDownregulation by Vitamin D Receptor Agonists

“…These results appear to contrast with previous data showing upregulation of CCL18 by vitamin D in monocyte-derived immature dendritic cells [ 52 ]. However, recent reports demonstrate that the modulation of immune signaling by vitamin D in human mononuclear phagocytes is cell-type-specific, with differential responses in monocytes, macrophages, and dendritic cells [ 53 ]. It is thus possible that opposite effects are found on the regulation of CCL18 by VDR agonists in different cellular systems.…”