Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D also mediates potent tolerogenic effects: it is generally believed that vitamin D attenuates inflammation and acquired immunity, and thus potentially limits collateral tissue damage. Nevertheless, several studies indicate that vitamin D promotes aspects of acquired host defense. Clinically, vitamin D deficiency has been associated with an increased risk for various infectious diseases in epidemiological studies; yet, robust data from controlled trials investigating the use of vitamin D as a preventive or therapeutic agent are missing. In this review, we summarize the current knowledge regarding the effect of vitamin D on innate and acquired host defense, and speculate on the difficulties to translate the available molecular medicine data into practical therapeutic or preventive recommendations.

Glucocorticoids are extensively used to treat inflammatory diseases; however, their chronic intake increases the risk for mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. In this study, we investigated the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial responses, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-γ, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis, we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-γ stimulation. This module was linked to the biological functions autophagy, phagosome maturation, and lytic vacuole/lysosome, and contained the vacuolar H+-ATPase subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast with IFN-γ, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the vacuolar H+-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy.

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation.

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Contact hypersensitivity (CHS) is a mouse model for human allergic contact dermatitis (ACD). Although human ACD lesions are frequently characterized by a mixed gene expression pattern of Th1 IFN-g and Th2 IL-4, a majority of murine CHS studies induced by strong model haptens have heavily focused on the role of Th1 IFN-g. Here, we found that oxazolone (Ox)-induced CHS model showed a mixed gene expression signature of IFN-g and IL-4, and type 2 cytokine IL-4 was associated with the severity of skin inflammation. Ox-induced lesional CHS skins demonstrated an increased gene expression level of cytokines and chemokines which belong to both Th1 and Th2 immunities. During the sensitization phase, IL-4 mRNA expression was markedly increased in the skin-draining lymph nodes at 72hr after a single topical application of Ox. The extent of ear thickness and transcript level of IL-4 were significantly lower in mice depleted with LangerineCD301bþ dermal dendritic cells (DCs), whereas local expression of IFN-g was comparable to that of control mice. Interestingly, Ox-induced CHS responses and local gene expression of IL-4 was not affected after by depletion of all Langerinþ DC subsets in the skin. Therefore, our findings suggest a novel insight for the possible role of type 2 immunity in Ox-induced CHS model, which is mediated by a specific subset of CD301bþ dermal dendritic cells in the skin.