title: Vitamin D induces interleukin-1β expression: paracrine macrophage epithelial signaling controls M. tuberculosis infection.
abstract: Although vitamin D deficiency is a common feature among patients presenting with active tuberculosis, the full scope of vitamin D action during Mycobacterium tuberculosis (Mtb) infection is poorly understood. As macrophages are the primary site of Mtb infection and are sites of vitamin D signaling, we have used these cells to understand the molecular mechanisms underlying modulation of the immune response by the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D). We found that the virulent Mtb strain H37Rv elicits a broad host transcriptional response. Transcriptome profiling also revealed that the profile of target genes regulated by 1,25D is substantially altered by infection, and that 1,25D generally boosts infection-stimulated cytokine/chemokine responses. We further focused on the role of 1,25D- and infection-induced interleukin 1β (IL-1β) expression in response to infection. 1,25D enhanced IL-1β expression via a direct transcriptional mechanism. Secretion of IL-1β from infected cells required the NLRP3/caspase-1 inflammasome. The impact of IL-1β production was investigated in a novel model wherein infected macrophages were co-cultured with primary human small airway epithelial cells. Co-culture significantly prolonged survival of infected macrophages, and 1,25D/infection-induced IL-1β secretion from macrophages reduced mycobacterial burden by stimulating the anti-mycobacterial capacity of co-cultured lung epithelial cells. These effects were independent of 1,25D-stimulated autophagy in macrophages but dependent upon epithelial IL1R1 signaling and IL-1β-driven epithelial production of the antimicrobial peptide DEFB4/HBD2. These data provide evidence that the anti-microbial actions of vitamin D extend beyond the macrophage by modulating paracrine signaling, reinforcing its role in innate immune regulation in humans.
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Verway
authors.forename: Manuella
authors.initials: M
authors.lastname: Bouttier
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Wang
authors.forename: Marilyn
authors.initials: M
authors.lastname: Carrier
authors.forename: Mario
authors.initials: M
authors.lastname: Calderon
authors.forename: Beum-Soo
authors.initials: BS
authors.lastname: An
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Devemy
authors.forename: Fiona
authors.initials: F
authors.lastname: McIntosh
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Behr
authors.forename: John H
authors.initials: JH
authors.lastname: White
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D019899:Paracrine Communication / Q000235:genetics / Q000276:immunology*; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014815:Vitamins / Q000494:pharmacology*; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C106641:DEFB4A protein, human; C513975:Defb4 protein, mouse; C508585:IL1B protein, human; C508590:IL1R1 protein, human; C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D053573:Receptors, Interleukin-1 Type I; D014815:Vitamins; D023083:beta-Defensins; D020170:Caspase 1; D002117:Calcitriol