tretinoin and Enterobacteriaceae-Infections

Good to excellent clinical results have been obtained in the treatment of severe inflammatory acne (acne conglobata, acne fulminans, and acne conglobata with hidradenitis and dissecting cellulitis of the scalp) with orally administered isotretinoin (13-cis-retinoic acid). Similar promising results have been obtained in patients with severe rosacea and gram-negative folliculitis. Isotretinoin probably has multiple modes of action, including (1) inhibition of sebaceous gland activity, (2) inhibition of the growth of Propionibacterium acnes within the follicle, although the retinoid is not antibacterial, (3) inhibition of inflammation, and (4) alteration of the pattern of keratinization within the follicle, as demonstrated by light and ultrastructural studies.

Topics: Acne Vulgaris; Adolescent; Adult; Clinical Trials as Topic; Enterobacteriaceae Infections; Female; Folliculitis; Humans; Isomerism; Isotretinoin; Male; Rosacea; Skin; Tretinoin

Group 3 innate lymphoid cells (ILC3s) control the formation of intestinal lymphoid tissues and play key roles in intestinal defense. They express neuropeptide vasoactive intestinal peptide (VIP) receptor 2 (VPAC2), through which VIP modulates their function, but whether VIP exerts other effects on ILC3 remains unclear. We show that VIP promotes ILC3 recruitment to the intestine through VPAC1 independent of the microbiota or adaptive immunity. VIP is also required for postnatal formation of lymphoid tissues as well as the maintenance of local populations of retinoic acid (RA)-producing dendritic cells, with RA up-regulating gut-homing receptor CCR9 expression by ILC3s. Correspondingly, mice deficient in VIP or VPAC1 suffer a paucity of intestinal ILC3s along with impaired production of the cytokine IL-22, rendering them highly susceptible to the enteric pathogen

Topics: Animals; Citrobacter rodentium; Dendritic Cells; Enterobacteriaceae Infections; Gastrointestinal Microbiome; Interleukin-22; Interleukins; Lymphocytes; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, CCR; Receptors, Vasoactive Intestinal Peptide, Type II; Tretinoin; Vasoactive Intestinal Peptide

Vitamin A (VA) deficiency remains prevalent in resource limited areas. Using Citrobacter rodentium infection in mice as a model for diarrheal diseases, previous reports showed reduced pathogen clearance and survival due to vitamin A deficient (VAD) status. To characterize the impact of preexisting VA deficiency on gene expression patterns in the intestines, and to discover novel target genes in VA-related biological pathways, VA deficiency in mice were induced by diet. Total mRNAs were extracted from small intestine (SI) and colon, and sequenced. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and co-expression network analyses were performed. DEGs compared between VAS and VAD groups detected 49 SI and 94 colon genes. By GO information, SI DEGs were significantly enriched in categories relevant to retinoid metabolic process, molecule binding, and immune function. Three co-expression modules showed significant correlation with VA status in SI; these modules contained four known retinoic acid targets. In addition, other SI genes of interest (e.g., Mbl2, Cxcl14, and Nr0b2) in these modules were suggested as new candidate genes regulated by VA. Furthermore, our analysis showed that markers of two cell types in SI, mast cells and Tuft cells, were significantly altered by VA status. In colon, "cell division" was the only enriched category and was negatively associated with VA. Thus, these data suggested that SI and colon have distinct networks under the regulation of dietary VA, and that preexisting VA deficiency could have a significant impact on the host response to a variety of disease conditions.

Topics: Animals; Citrobacter rodentium; Colon; Enterobacteriaceae Infections; Gene Expression Profiling; Gene Ontology; Intestine, Small; Mice; Mice, Inbred C57BL; RNA-Seq; RNA, Messenger; Transcriptome; Tretinoin; Vitamin A; Vitamin A Deficiency

Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor α (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack of RARα resulted in increased KLF4

Topics: Animals; Cell Differentiation; Cells, Cultured; Citrobacter rodentium; Enterobacteriaceae Infections; Goblet Cells; Homeostasis; Intestinal Mucosa; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Mice; Mice, Inbred C57BL; Mice, Knockout; Mononuclear Phagocyte System; Pancreatitis-Associated Proteins; Retinoic Acid Receptor alpha; Signal Transduction; Tretinoin; Zebrafish

The intestinal immune system must be able to respond to a wide variety of infectious organisms while maintaining tolerance to non-pathogenic microbes and food antigens. The Vitamin A metabolite all-trans-retinoic acid (atRA) has been implicated in the regulation of this balance, partially by regulating innate lymphoid cell (ILC) responses in the intestine. However, the molecular mechanisms of atRA-dependent intestinal immunity and homeostasis remain elusive. Here we define a role for the transcriptional repressor Hypermethylated in cancer 1 (HIC1, ZBTB29) in the regulation of ILC responses in the intestine. Intestinal ILCs express HIC1 in a vitamin A-dependent manner. In the absence of HIC1, group 3 ILCs (ILC3s) that produce IL-22 are lost, resulting in increased susceptibility to infection with the bacterial pathogen Citrobacter rodentium. Thus, atRA-dependent expression of HIC1 in ILC3s regulates intestinal homeostasis and protective immunity.

Topics: Animals; Citrobacter rodentium; Enterobacteriaceae Infections; Gene Expression Regulation; Homeostasis; Immunity, Innate; Intestines; Kruppel-Like Transcription Factors; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Signal Transduction; Tretinoin

Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2, and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to migration to the intestine ILCs first undergo a "switch" in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term population and effector function of ILCs in the intestine. Only ILC1 and ILC3, but not ILC2, undergo the RA-dependent homing receptor switch in gut-associated lymphoid tissues. In contrast, ILC2 acquire gut homing receptors in a largely RA-independent manner during their development in the bone marrow and can migrate directly to the intestine. Thus, distinct programs regulate the migration of ILC subsets to the intestine for regulation of innate immunity.

Topics: Animals; Cell Movement; Cells, Cultured; Citrobacter rodentium; Dendritic Cells; Enterobacteriaceae Infections; Immunity, Innate; Intestinal Mucosa; Intestines; Lymphocyte Subsets; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, CCR; Receptors, CCR7; Tretinoin

Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22-responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti-IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.

Topics: Animals; Antibodies, Neutralizing; Citrobacter rodentium; Colitis; Colon; Dextran Sulfate; Enterobacteriaceae Infections; Inflammation; Interleukin-22; Interleukins; Lymphocytes; Mice; Mice, Inbred C57BL; Promoter Regions, Genetic; Protein Binding; Receptors, Antigen, T-Cell, gamma-delta; Receptors, Retinoic Acid; T-Lymphocytes, Helper-Inducer; Transcription, Genetic; Tretinoin

The gut mucosa hosts large numbers of activated lymphocytes that are exposed to stimuli from the diet, microbiota and pathogens. Although CD4(+) T cells are crucial for defense, intestinal homeostasis precludes exaggerated responses to luminal contents, whether they are harmful or not. We investigated mechanisms used by CD4(+) T cells to avoid excessive activation in the intestine. Using genetic tools to label and interfere with T cell-development transcription factors, we found that CD4(+) T cells acquired the CD8-lineage transcription factor Runx3 and lost the CD4-lineage transcription factor ThPOK and their differentiation into the T(H)17 subset of helper T cells and colitogenic potential, in a manner dependent on transforming growth factor-β (TGF-β) and retinoic acid. Our results demonstrate considerable plasticity in the CD4(+) T cell lineage that allows chronic exposure to luminal antigens without pathological inflammation.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8 Antigens; Cell Differentiation; Cells, Cultured; Citrobacter rodentium; Colitis; Core Binding Factor Alpha 3 Subunit; Enterobacteriaceae Infections; Homeodomain Proteins; Inflammation; Intestinal Mucosa; Intestines; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Tamoxifen; Transcription Factors; Transforming Growth Factor beta; Tretinoin