Indole-3-Carbinol-Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in premature infants; therefore, the identification of therapeutic and preventative strategies against NEC remains a high priority. The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) is well known to contribute to the regulation of intestinal microbial communities and amelioration of intestinal inflammation. However, the role of AhR signaling in NEC is unclear. Experimental NEC was induced in 4-d-old wild-type mice or mice lacking AhR expression in the intestinal epithelial cells or AhR expression in CD11c+ cells (AhRΔCD11c) by subjecting animals to twice daily hypoxic stress and gavage feeding with formula supplemented with LPS and enteric bacteria. During NEC, compared with wild-type mice treated with vehicle, littermates treated with an AhR proligand, indole-3-carbinol, had reduced expression of Il1b and Marco, a scavenger receptor that mediates dendritic cell activation and the recognition and clearance of bacterial pathogens by macrophages. Furthermore, indole-3-carbinol treatment led to the downregulation of genes involved in cytokine and chemokine, as revealed by pathway enrichment analysis. AhR expression in the intestinal epithelial cells and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhRΔCD11c mice with NEC exhibited heightened inflammatory responses compared with their cre-negative mouse littermates. In seeking to determine the mechanisms involved in this increased inflammatory response, we identified the Tim-4- monocyte-dependent subset of macrophages as increased in AhRΔCD11c mice compared with their cre-negative littermates. Taken together, these findings demonstrate the potential for AhR ligands as a novel immunotherapeutic approach to the management of this devastating disease.

IL-33 and the intestine: The good, the bad, and the inflammatory.

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that has been widely studied since its discovery in 2005 for its dichotomous functions in homeostasis and inflammation. IL-33, along with its receptor suppression of tumorigenicity 2 (ST2), has been shown to modulate both the innate and adaptive immune system. Originally, the IL-33/ST2 signaling axis was studied in the context of inducing type 2 immune responses with the expression of ST2 by T helper 2 (TH2) cells. However, the role of IL-33 is not limited to TH2 responses. Rather, IL-33 is a potent activator of TH1 cells, group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, and CD8+ T cells. The intestine is uniquely important in this discussion, as the intestinal epithelium is distinctively positioned to interact with both pathogens and the immune cells housed in the mucosa. In the intestine, IL-33 is expressed by the pericryptal fibroblasts and its expression is increased particularly in disease states. Moreover, IL-33/ST2 signaling aberrancy is implicated in the pathogenesis of inflammatory bowel disease (IBD). Accordingly, for this review, we will focus on the role of IL-33 in the regulation of intestinal immunity, involvement in intestinal disease, and implication in potential therapeutics.

The Role of Mucosal Immunity in the Pathogenesis of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of prematurity. Although the precise cause is not well understood, the main risk factors thought to contribute to NEC include prematurity, formula feeding, and bacterial colonization. Recent evidence suggests that NEC develops as a consequence of intestinal hyper-responsiveness to microbial ligands upon bacterial colonization in the preterm infant, initiating a cascade of aberrant signaling events, and a robust pro-inflammatory mucosal immune response. We now have a greater understanding of important mechanisms of disease pathogenesis, such as the role of cytokines, immunoglobulins, and immune cells in NEC. In this review, we will provide an overview of the mucosal immunity of the intestine and the relationship between components of the mucosal immune system involved in the pathogenesis of NEC, while highlighting recent advances in the field that have promise as potential therapeutic targets. First, we will describe the cellular components of the intestinal epithelium and mucosal immune system and their relationship to NEC. We will then discuss the relationship between the gut microbiota and cell signaling that underpins disease pathogenesis. We will conclude our discussion by highlighting notable therapeutic advancements in NEC that target the intestinal mucosal immunity.

A systematic review of sinonasal oncocytomas and oncocytic carcinomas: Diagnosis, management, and technical considerations.

BACKGROUND: Oncocytomas and oncocytic carcinomas are rare tumors of the sinonasal cavity with the propensity for local invasion. This report and systematic review details a case of a nasal oncocytoma involving the lacrimal sac and provides an update of the current literature. METHODS: A systematic literature review was performed using PubMed and Ovid databases. The data obtained from published articles with sinonasal oncocytoma/oncocytic carcinoma as the primary diagnosis included patient demographics, presentation, radiographic and histologic findings, management, and recurrence rates. RESULTS: Twenty cases were identified. The most common symptoms were epistaxis (n = 11) and nasal obstruction (n = 11). Involvement of the nasal cavity was most common (n = 17), followed by the paranasal sinuses (n = 13) and nasolacrimal apparatus (n = 4). Recurrence occurred in 55% of cases. Recurrence was associated with invasion or infiltration found on histology or the presence of both invasion/infiltration and mitotic figures/pleomorphism (p < 0.05), with no significant relationship between recurrence and age at diagnosis (p = 0.42), sex (p = 0.65), and location of tumor (p = 0.14). The authors present the case of a 73-year-old woman with a 5-month history of worsening epistaxis and biopsy-proven oncocytoma. Complete surgical resection of the tumor using combined endonasal endoscopic and anterior orbitotomy approach is described. CONCLUSION: Oncocytomas and oncocytic carcinomas are rare tumors of the sinonasal cavity with a high rate of local recurrence and orbital involvement. Surgical resection is the treatment of choice and complete resection can be achieved with an endoscopic endonasal approach.

Interleukin-22 Signaling in the Regulation of Intestinal Health and Disease.

Interleukin (IL)-22 is a member of the IL-10 family of cytokines that has been extensively studied since its discovery in 2000. This review article aims to describe the cellular sources and signaling pathways of this cytokine as well as the functions of IL-22 in the intestine. In addition, this article describes the roles of IL-22 in the pathogenesis of several gastrointestinal diseases, including inhibition of inflammation and barrier defense against pathogens within the intestine. Since many of the functions of IL-22 in the intestine are incompletely understood, this review is meant to assess our current understanding of the roles of IL-22 and provide new opportunities for inquiry to improve human intestinal health and disease.