model 1) each LPS- and BG-treated PBMCs initiate phagocytosis, but LPSchallenged cells CYP26 Formulation activate proliferation and cell migration, although BG-treated cells differentiate. In contrast, a pre-treatment with vitamin D (model two) reduces the activating effects of both LPS and BG on cytokine signaling too as on inflammation and together with BG it activates phagocytosis. Interestingly, the simultaneous therapy with immune challenges and vitamin D (model 3) causes in case of LPS the inhibition of cytokine signaling and with BG the induction of differentiation. In all 3 models the co-treatment considerably adjustments the functional outcomes of immune challenges, which are directed towards disease- and pathogen-specific responses. Hence, one of the most disease-preventive reactions are triggered by a pre-treatment with vitamin D (model two). In conclusion, this study offers a transcriptome-wide view how vitamin D modulates responses on the innate immune program to immune challenges like bacterial and fungal infections. A pre-treatment with vitamin D (model two) appearsFrontiers in Immunology | frontiersin.orgDecember 2021 | Volume 12 | ArticleMalmberg et al.Vitamin D Remedy Sequence Is CriticalFIGURE 5 | Summary of key responsive genes. LPS, BG and 1,25(OH)2D3 (125D) responsive genes are categorized primarily based on their response to unique remedies in diverse models. Circle 1: genes that happen to be responsive to all treatments and models, circle two: genes which can be responsive to all remedies but not in each and every model, circle 3: genes which can be responsive to at least two stimuli and their combination and circle 4: genes which might be specifically responsive to stimuli. The gene positions in relation to colored sectors represent their preferences to the indicated stimuli. Genes are color-coded primarily based on the principal cellular location of their protein merchandise. Blue: LPS, purple: BG, red: 1, be extra helpful than its application soon after microbial challenges, like infections with pathogens. Vitamin D3 supplementation will increase the vitamin D status of a person and make vitamin D signaling by way of VDR and its target genes far more productive. Given that a sizable number of these responsive genes are involved in improving the functionality of immunity, their vitamin D-triggered activity is often thought of as training of in distinct the innate immune system (43). This suggests that vitamin D3 supplementation might have animportant role in preventing infectious ailments or decreasing their serious consequences.Data AVAILABILITY STATEMENTThe datasets presented within this study might be found in on the net repositories. The names of your repository/K-Ras review repositories andFrontiers in Immunology | frontiersin.orgDecember 2021 | Volume 12 | ArticleMalmberg et al.Vitamin D Treatment Sequence Is Criticalaccession quantity(s) may be identified within the article/ Supplementary Material.FUNDINGCC had been supported by the Academy of Finland (grant No. 267067).ETHICS STATEMENTThe research involving human participants have been reviewed and approved by the analysis ethics committee from the Northern Savo Hospital District had authorized the study protocol (#9/2014). The patients/participants provided their written informed consent to take part in this study.ACKNOWLEDGMENTSThe authors thank the Gene Core facility in the EMBL in Heidelberg, Germany, for massively parallel sequencing services and RNA-seq read alignment. The sequence read processing and alignment have been run around the servers offered by Bioinformatics Center, University o