Vitamin D differentially regulatesSalmonella-induced intestine epithelial autophagy and interleukin-1β expression

Abstract

AIMTo investigate the effects of active vitamin D3 on autophagy and interleukin (IL)-1β expression in Salmonella-infected intestinal epithelial cells (IECs).METHODSCaco-2 cells, NOD2 siRNA-, Atg16L1 siRNA- or vitamin D receptor (VDR) siRNA-transfected Caco-2 cells were pretreated with 1,25-dihydroxyvitamin D3 (1,25D3), and then infected by wild-type S. typhimurium strain SL1344. The conversion of LC3-I to LC3-II was detected by Western blot analysis and LC3+ autophagosome was analyzed by immunofluorescence. Caco-2 cells or VDR siRNA-transfected cells were pretreated with 1,25D3, and then infected by SL1344. Membrane protein and total RNA were analyzed by Western blot and RT-PCR for VDR and Atg16L1 protein and mRNA expression, respectively. Atg16L1 siRNA-transfected Caco-2 cells were pretreated by 1,25D3 and then infected with SL1344. Total RNA was analyzed by RT-PCR for IL-1β mRNA expression.RESULTSThe active form of vitamin D, 1,25D3, showed enhanced VDR-mediated Atg16L1 mRNA expression, membranous Atg16L1 protein expression leading to enhanced autophagic LC3II protein expression and LC3 punctae in Salmonella-infected Caco-2 cells which was counteracted by Atg16L1 and VDR siRNA, but Atg16L1 mediated suppression of IL-1β expression. Thus, active vitamin D may enhance autophagy but suppress inflammatory IL-1β expression in Salmonella-infected IECs.CONCLUSIONActive vitamin D might enhance autophagic clearance of Salmonella infection, while modulation of inflammatory responses prevents the host from detrimental effects of overwhelming inflammation.

Vitamin D in Acute Campylobacteriosis–Results From an Intervention Study Applying a Clinical Campylobacter jejuni Induced Enterocolitis Model

“…Due to the pleiotropic beneficial effects of vitamin D in health and disease, the application of vitamin D as safe dietary supplement is currently discussed as promising option for the adjunct treatment and prophylaxis of various immunopathological morbidities including infectious diseases, intestinal inflammatory conditions, and cancer, for instance (33, 55). In our present vitamin D intervention study applying a clinical acute campylobacteriosis model, prophylactic synthetic 25-OH-cholecalciferol application starting 4 days prior murine infection resulted in dampened C. jejuni induced intestinal and extra-intestinal inflammatory sequalae, but could not lower the high intestinal pathogen loads of more than 10 9 viable C. jejuni per g feces.…”

“…The identification of the vitamin D receptor (VDR) on peripheral blood mononuclear cells in the 1980s first pointed to immune-related functions of vitamin D (28, 29). In fact, vitamin D has been shown to be involved in modulating both, innate and adaptive immune responses (30–33) and to exert anti-inflammatory effects (34). Furthermore, several reports underline the anti-microbial properties of vitamin D (33).…”

“…In fact, vitamin D has been shown to be involved in modulating both, innate and adaptive immune responses (30–33) and to exert anti-inflammatory effects (34). Furthermore, several reports underline the anti-microbial properties of vitamin D (33). For instance, vitamin D could effectively inhibit the growth of Gram-positive bacterial strains such as Staphylococcus aureus, Streptococcus pyogenes , and Streptococcus mutans , but also of Gram-negative species including Klebsiella pneumoniae and Escherichia coli (35–37).…”

Salmonella Interacts With Autophagy to Offense or Defense

“…Moreover, biochanin A (BCA), a polyphenolic compound found in certain species of plants, has been proven to target Salmonella infection through AMPK/ULK1/mTOR-mediated autophagy, extracellular traps, and the reversal of SPI-1dependent macrophage M2 polarization (Zhao et al, 2018). In addition, Huang (2016) found that 1,25-dihydroxyvitamin D3 may promote the autophagic removal of intracellular Salmonella and modulate inflammatory responses to prevent the host from the adverse effects of excessive inflammation. Kim et al (2018) evaluated the antibacterial effect of bioprocessed (fermented) rice bran extract (BPRBE) against Salmonella Typhimurium infection, and investigated the mechanisms involved.…”

Artesunate interacts with the vitamin D receptor to reverse sepsis‐induced immunosuppression in a mouse model via enhancing autophagy

“…However, we observed tight binding between VDR and Atg16l1 promotor, leading to low ATG16L1 protein levels in LPS‐tolerant cells, demonstrating negative regulation by VDR on Atg16l1 transcription in LPS‐tolerant cells, which did not change in presence of V D3 . Most effects of VDR on ATG16L1 and autophagy were investigated in epithelial cells (Huang, 2016; Sun, 2016) but not in monocytes/macrophages. Our study focused on the immunosuppression stage in monocytes/macrophages, unlike the parenchyma cells such as epithelial cells which were not immunosuppressed.…”