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1.  Selective modulation of autophagy, innate immunity and adaptive immunity by small molecules 
ACS chemical biology  2013;8(12):2724-2733.
Autophagy is an evolutionarily conserved catabolic process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. Autophagy acts at the intersection of pathways involved in cellular stress, host defense, and modulation of inflammatory and immune responses; however, the details of how the autophagy network intersects with these processes remain largely undefined. Given the role of autophagy in several human diseases, it is important to determine the extent to which modulators of autophagy also modify inflammatory or immune pathways, and whether it is possible to modulate a subset of these pathways selectively. Here, we identify small-molecule inducers of basal autophagy (including several FDA-approved drugs) and characterize their effects on IL-1β production, autophagic engulfment and killing of intracellular bacteria, and development of Treg, TH17, and TH1 subsets from naïve T cells. Autophagy inducers with distinct, selective activity profiles were identified that reveal the functional architecture of connections between autophagy, and innate and adaptive immunity. In macrophages from mice bearing a conditional deletion of the essential autophagy gene Atg16L1, the small molecules inhibit IL-1β production to varying degrees suggesting that individual compounds may possess both autophagy-dependent and autophagy-independent activity on immune pathways. The small molecule autophagy inducers constitute useful probes to test the contributions of autophagy-related pathways in diseases marked by impaired autophagy or elevated IL-1β, and to test novel therapeutic hypotheses.
PMCID: PMC3951132  PMID: 24168452
2.  The Microbiota and Inflammatory Bowel Disease: Insights from Animal Models 
Anaerobe  2013;24:10.1016/j.anaerobe.2013.04.006.
Inflammatory bowel disease (IBD) is thought to result from a dysregulated immune response to intestinal microbial flora in individuals with genetic predisposition(s). Genome wide association studies (GWAS) in human IBD have identified more than 150 associated loci, some of which are key players in innate immunity and bacterial handling, reflecting the importance of the microbiota in disease pathogenesis. In fact, the presence of a microbial flora is not only crucial to the development of a normal murine immune system but also critical for the development of disease in the majority of animal models of IBD.
Although animal models do not perfectly recapitulate human IBD, they have led to the discovery of important concepts in IBD pathogenesis, such as the central role of microbiota in disease development and perpetuation. Many genetically susceptible models do not develop colitis when raised in a germ-free or Helicobacter-free environment. In fact, disease in most models can be attenuated or completely abolished with antibiotic treatment. Moreover, an interplay between intestinal microbiota and mucosal immune activation is suggested by the presence of serum antibodies against the Cbir1 flagellin, an immunodominant antigen that activates TLR5, in certain models of spontaneous colitis as well as in human patients. Furthermore, T cells reactive to Cbir1 are able to induce disease in recipient mice upon adoptive cell transfer, demonstrating the pro-inflammatory properties of certain bacterial products. In fact, it has been shown that transfer of certain intestinal bacteria from a specific genetically altered mouse model with spontaneous colitis can induce disease in wild-type mice upon co-housing or direct feeding. These observations demonstrate the pathogenic potential of intestinal microbiota in IBD.
However, intestinal bacteria are not always maladaptive in mucosal homeostasis. Both Bacteroides fragilis and Clostridium species promote the number and function of a certain regulatory T cell subset in the colon leading to protection against murine colitis. In fact, normal development of regulatory cells and epithelial cell integrity are abolished in the absence of an intestinal flora, suggestive of the need for certain microbial components to induce beneficial anti-inflammatory mechanisms.
All in all, altered immune responses to microbes play a crucial role in IBD pathogenesis. However, certain components of the microbiota are also likely critical for normal development of regulatory mechanisms that contribute to mucosal homeostasis. Findings in animal models highlight the concept that IBD is a disease that results from the interplay of genetics and microbial/environmental factors.
PMCID: PMC3766478  PMID: 23603043
3.  Atg16l1 is Required for Autophagy in Intestinal Epithelial Cells and Protection of Mice from Salmonella Infection 
Gastroenterology  2013;145(6):10.1053/j.gastro.2013.08.035.
Background & Aims
Intestinal epithelial cells aid in mucosal defense by providing a physical barrier against entry of pathogenic bacteria and secreting anti-microbial peptides (AMPs). Autophagy is an important component of immune homeostasis. However, little is known about its role in specific cell types during bacterial infection in vivo. We investigated the role of autophagy in the response of intestinal epithelial and antigen-presenting cells to Salmonella infection in mice.
We generated mice deficient in Atg16l1 in epithelial cells (Atg16l1f/f x Villin-cre) or CD11c+ cells (Atg16l1f/f x CD11c-cre); these mice were used to assess cell type-specific, anti-bacterial autophagy. All responses were compared to Atg16l1f/f mice (controls). Mice were infected with Salmonella enterica serovar Typhimurium; cecum and small intestine tissues were collected for immunofluorescence, histology, and quantitative reverse transcription PCR analyses of cytokines and AMPs. Modulators of autophagy were screened to evaluate their effects on anti-bacterial responses in human epithelial cells.
Autophagy was induced in small intestine and cecum following infection with S Typhimurium, and required Atg16l1. S Typhimurium colocalized with microtubule-associated protein 1 light chain 3 beta (Map1lc3b or LC3) in the intestinal epithelium of control mice but not in Atg16l1f/f x Villin-cre mice. Atg16l1f/f x Villin-cre mice also had fewer Paneth cells and abnormal granule morphology, leading to reduced expression of AMP. Consistent with these defective immune responses, Atg16l1f/f x Villin-cre mice had increased inflammation and systemic translocation of bacteria compared with control mice. In contrast, we observed few differences between Atg16l1f/f x CD11c-cre and control mice. Trifluoperazine promoted autophagy and bacterial clearance in HeLa cells; these effects were reduced upon knockdown of ATG16L1.
Atg16l1 regulates autophagy in intestinal epithelial cells and is required for bacterial clearance. It is also required to prevent systemic infection of mice with enteric bacteria.
PMCID: PMC3840157  PMID: 23973919
mouse model; autophagy; intestinal barrier; mucosa
4.  More than Skin Deep 
PMCID: PMC3614151  PMID: 22878853
dermatology; infectious disease; arthritis; medical education cognition; problem solving
5.  Diagnostic Ionizing Radiation Exposure in a Population-Based Cohort of Patients with Inflammatory Bowel Disease 
For diagnosis, assessing disease activity, complications and extraintestinal manifestations, and monitoring response to therapy, patients with inflammatory bowel disease undergo many radiological studies employing ionizing radiation. However, the extent of radiation exposure in these patients is unknown.
A population-based inception cohort of 215 patients with inflammatory bowel disease from Olmsted County, Minnesota, diagnosed between 1990 and 2001, was identified. The total effective dose of diagnostic ionizing radiation was estimated for each patient. Linear regression was used to assess the median total effective dose since symptom onset.
The number of patients with Crohn's disease and ulcerative colitis was 103 and 112, with a mean age at diagnosis of 38.6 and 39.4 yr, respectively. Mean follow-up was 8.9 yr for Crohn's disease and 9.0 yr for ulcerative colitis. Median total effective dose for Crohn's disease was 26.6 millisieverts (mSv) (range, 0–279) versus 10.5 mSv (range, 0–251) for ulcerative colitis (P < 0.001). Computed tomography accounted for 51% and 40% of total effective dose, respectively. Patients with Crohn's disease had 2.46 times higher total effective dose than ulcerative colitis patients (P = 0.001), adjusting for duration of disease.
Annualizing our data, the radiation exposure in the inflammatory bowel disease population was equivalent to the average annual background radiation dose from naturally occurring sources in the U.S. (3.0 mSv). However, a subset of patients had substantially higher doses. The development of imaging management guidelines to minimize radiation dose, dose-reduction techniques in computed tomography, and faster, more robust magnetic resonance techniques are warranted.
PMCID: PMC2831296  PMID: 18564113

Results 1-5 (5)