Species-specific regulation of innate immunity by vitamin D signaling

Dimitrov, V.; White, John H.

doi:10.1016/j.jsbmb.2015.09.016

Cited by 89 publications

(76 citation statements)

References 38 publications

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“…S4A), while 111 genes were exclusively regulated in mouse organoids (Table S6). This result agrees with the reported lack of conservation of VDR response elements between primates and rodents [26]. We also show that the calcitriol expression profile in wt mouse organoids was related with the Mex3a high /Lgr5 high mouse signature of slow-dividing intestinal stem cells [22] ( Fig.…”

Section: Calcitriol Differentially Modulates Cell Phenotype and Prolisupporting

confidence: 92%

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

et al. 2019

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Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25‐dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids, calcitriol upregulates stemness‐related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7, and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness‐related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.

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Section: Calcitriol Differentially Modulates Cell Phenotype and Prolisupporting

confidence: 92%

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

et al. 2019

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“…For instance, in mouse macrophages, the expression of inducible NO synthase and the production of NO (25–27), a fundamental murine anti-mycobacterial molecule, are significantly reduced by glucocorticoids (28, 29). We and others previously reported that in humans, but not in mice, the vitamin D–mediated induction of cathelicidin antimicrobial peptide has a central role in the antimycobacterial activity in macrophages (6, 7, 14, 30, 31). Thus, we compared the ability of dexamethasone and IFN-γ to induce cathelicidin.…”

Section: Resultsmentioning

confidence: 93%

Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity againstMycobacterium bovisBacille Calmette–Guérin in Glucocorticoid-Treated Human Macrophages

Steiger

Stephan

Inkeles

et al. 2016

The Journal of Immunology

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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.

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“…This insertion has been retained in both old- and new-world primates (63). This event was a key element in the evolution of human/primate-specific mechanisms of innate immune regulation by vitamin D signaling (64). …”

Section: Discussionmentioning

confidence: 99%

Alu repeats as transcriptional regulatory platforms in macrophage responses toM. tuberculosisinfection

et al. 2016

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To understand the epigenetic regulation of transcriptional response of macrophages during early-stage M. tuberculosis (Mtb) infection, we performed ChIPseq analysis of H3K4 monomethylation (H3K4me1), a marker of poised or active enhancers. De novo H3K4me1 peaks in infected cells were associated with genes implicated in host defenses and apoptosis. Our analysis revealed that 40% of de novo regions contained human/primate-specific Alu transposable elements, enriched in the AluJ and S subtypes. These contained several transcription factor binding sites, including those for members of the MEF2 and ATF families, and LXR and RAR nuclear receptors, all of which have been implicated in macrophage differentiation, survival, and responses to stress and infection. Combining bioinformatics, molecular genetics, and biochemical approaches, we linked genes adjacent to H3K4me1-associated Alu repeats to macrophage metabolic responses against Mtb infection. In particular, we show that LXRα signaling, which reduced Mtb viability 18-fold by altering cholesterol metabolism and enhancing macrophage apoptosis, can be initiated at response elements present in Alu repeats. These studies decipher the mechanism of early macrophage transcriptional responses to Mtb, highlighting the role of Alu element transposition in shaping human transcription programs during innate immunity.

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Species-specific regulation of innate immunity by vitamin D signaling

Cited by 89 publications

References 38 publications

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids

Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity againstMycobacterium bovisBacille Calmette–Guérin in Glucocorticoid-Treated Human Macrophages

Alu repeats as transcriptional regulatory platforms in macrophage responses toM. tuberculosisinfection

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