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Inflammatory Bowel Diseases (IBD) are a group of intestinal disorders which are increasing in prevalence in industrialized countries. Dynamics of intestinal inflammatory disorders are manifold and investigation of coherences might help developing new therapeutic strategies harnessing the acquired knowledge. Keeping a homeostatic balance in the intestinal environment is vital for normal gut functions, regulating inflammatory and anti-inflammatory processes. Dendritic cells are known as key players in the regulation of intestinal homeostasis as they scavenge their surroundings for antigens followed by the induction of an adaptive immune response. The aim of this study was to investigate the functional properties of resident lamina propria myeloid dendritic cells (mLPDCs) in the shift from a homeostatic to an inflammatory milieu. Utilization of an organ culture model (LEL) made it possible to collect migratory lamina propria mDCs from an acute inflammatory environment. Gene expression analysis of LEL mDCs compared to peripheral blood DCs (PBDCs) revealed a variety of functions attributed to their environment and activation status. The LEL mDCs showed a gene expression profile which hinted at contribution to tissue remodeling and wound healing processes. Moreover, the majority of emigrated LEL mDCs could be attributed to the cDC2 fraction of DCs which exhibit mostly anti-inflammatory functionalities. Upregulation of the IL-12 family member mRNAs encoding for the protein subunits IL-23p19 and EBI3 was striking, hinting at the formation of the newly discovered heterodimeric cytokine IL-39. Both subunit proteins could be detected in LEL mDCs but not in PBDCs. Experiments using recombinant proteins confirmed IL-39 heterodimer formation in vitro as well as in cell culture experiments. However, technical difficulties prevented confirmation of heterodimer presence in primary human lamina propria mDCs. Scientific publications and initial experiments might hint at a possible contribution to wound healing processes related to IL-39 or its subunits. A follow up experiment explored the gene expression profiles of mLPDCs from enzymatically digested IBD patients biopsies under inflammatory and non-inflammatory conditions as well as in healthy individuals. The extracted cells displayed a mixture of cDC1 and cDC2 cells with conserved functional properties across all samples including MHCII dependent antigen presentation and T cell regulatory processes amongst others. The gene expression analysis uncovered new aspects of mLPDCs including involvement in epithelial cell proliferation, humoral immunity and neuronal system development and signaling. Epithelial cell proliferation might contribute to wound healing properties of mLPDCs. Furthermore, the data hints at a mutual influence between mLPDCs and neuronal cells. Another striking observation was the detection of immunoglobulin related mRNAs hinting at yet unexplored functional properties of mLPDCs involving the expression of antibodies. Moreover, differential gene expression in mLPDCs varied for different IBD patient groups compared to healthy individuals.

Introduction Hyporesponsiveness of human lamina propria immune cells to microbial and nutritional antigens represents one important feature of intestinal homeostasis. It is at least partially mediated by low expression of the innate response receptors CD11b, CD14, CD16 as well as the cystine‐glutamate transporter xCT on these cells. Milieu‐specific mechanisms leading to the down‐regulation of these receptors on circulating monocytes, the precursor cells of resident macrophages, are mostly unknown. Methods Here, we addressed the question whether the short chain fatty acid n‐butyrate, a fermentation product of the mammalian gut microbiota exhibiting histone deacetylase inhibitory activity, is able to modulate expression of these receptors in human circulating monocytes. Results Exposure to n‐butyrate resulted in the downregulation of CD11b, CD14, as well as CD16 surface expression on circulating monocytes. XCT transcript levels in circulating monocytes were also reduced following exposure to n‐butyrate. Importantly, treatment resulted in the downregulation of protein and gene expression of the transcription factor PU.1, which was shown to be at least partially required for the expression of CD16 in circulating monocytes. PU.1 expression in resident macrophages in situ was observed to be substantially lower in healthy when compared to inflamed colonic mucosa. Conclusions In summary, the intestinal microbiota may support symbiosis with the human host organism by n‐butyrate mediated downregulation of protein and gene expression of innate response receptors as well as xCT on circulating monocytes following recruitment to the lamina propria. Downregulation of CD16 gene expression may at least partially be caused at the transcriptional level by the n‐butyrate mediated decrease in expression of the transcription factor PU.1 in circulating monocytes.