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Providing efficacious human immunodeficiency virus (HIV) prevention services to HIV-positive individuals is an appropriate strategy to reduce new infections. The Centers for Disease Control and Prevention (CDC) has identified interventions with evidence of efficacy for prevention with positives (PwP). Through its process of disseminating evidence-based interventions (EBIs), CDC has attempted to diffuse four of these interventions into practice. One of these interventions has been diffused to community-based organizations, whereas another has been diffused to medical clinics serving HIV-positive people. A third intervention was originally developed with HIV-positive individuals using methadone, but uptake by methadone clinics has not occurred. A fourth intervention for HIV-positive adolescents and young adults has had disappointing adoption levels. Unique implementation challenges have been encountered in various intervention settings. Lessons learned in the dissemination of the first four PwP interventions will facilitate implementation of three new PwP EBIs currently being packaged for dissemination. [ABSTRACT FROM AUTHOR]

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4 + T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4 + T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen T H 1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating T H 1-mediated inflammation., (© 2024. The Author(s).)

Ensuring good quality of life (QoL) among persons with diagnosed HIV (PWH) is a priority of the National HIV/AIDS Strategy (NHAS), which established 2025 goals for improving QoL. Goals are monitored through five indicators: self-rated health, unmet needs for mental health services, unemployment, hunger or food insecurity, and unstable housing or homelessness. Among the growing population of PWH aged ≥50 years, progress toward these goals has not been assessed. Data collected during the 2017-2022 cycles of the Medical Monitoring Project, an annual complex sample survey of U.S. adults with diagnosed HIV, assessed progress toward NHAS 2025 QoL goals among PWH aged ≥50 years, overall and by age group. The recent estimated annual percentage change from baseline (2017 or 2018) to 2022 was calculated for each indicator. Among PWH aged ≥50 years, the 2025 goal of 95% PWH with good or better self-rated health is 46.2% higher than the 2022 estimate. The 2025 goals of a 50% reduction in the other indicators range from 26.3% to 56.3% lower than the 2022 estimates. Decreasing hunger or food insecurity by 50% among PWH aged ≥65 was the only goal met by 2022. If recent trends continue, other NHAS QoL 2025 goals are unlikely to be met. Multisectoral strategies to improve access to housing, employment, food, and mental health will be needed to meet NHAS 2025 goals for QoL among older PWH., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

This systematic review synthesized published literature (2000 - 2023) to identify HIV interventions specifically designed for transgender persons in the United States (PROSPERO registration number: CRD42021256460). The review also summarized strategies for improving outcomes related to the four pillars of the Ending the HIV Epidemic (EHE) initiative in the United States: Diagnose, Treat, Prevent, and Respond. A comprehensive search was conducted using the Centers for Disease Control and Prevention's HIV Prevention Research Synthesis Project database, which included over 120,000 citations from routine systematic searches in CINAHL, EMBASE, Global Health, MEDLINE, PsycInfo, and Sociological Abstracts. Of 23 interventions that met inclusion criteria, 94% focused on transgender women of color and 22% focused on young transgender persons aged 15-29 years old. Most interventions focused on Treat or Prevent, few focused on Diagnosis, and none focused on Respond. Twenty interventions (87%) showed improvement in at least one EHE related outcome and a quarter of these effective interventions were tested with randomized controlled trials. Common strategies observed in effective interventions include the following: engaging the community in intervention development; pilot-testing with the focus population to ensure appropriateness and acceptability; addressing social determinants of health (e.g. stigma, discrimination, violence) through empowerment and gender-affirming approaches; increasing access to care, prevention, and services through co-location and one-stop shop models; and utilizing peer-led counseling, education, support, and navigation. Continuous effort is needed in addressing gaps, including more research for transgender men and rural settings and for how best to adopt and adapt best practices for subgroups of transgender population., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The prevalence of inflammatory bowel disease (IBD) has increased dramatically in recent years, particularly in pediatric populations. Successful remission with current therapies is limited and often transient, leading patients to seek alternative therapies for symptom relief, including the use of medical marijuana ( Cannabis sativa ). However, chronic cannabis use among IBD patients is associated with increased risk for surgical interventions. Therefore, determining the direct impact of cannabis use on immune modulation in IBD patients is of critical importance. Peripheral blood mononuclear cells of cannabis using and non-using pediatric IBD patients were phenotyped by flow cytometry and functionally assessed for their cytokine production profile. A phospho-kinase array was also performed to better understand changes in immune responses. Results were then compared with serum phytocannabinoid profiles of each patient to identify cannabinoid-correlated changes in immune responses. Results demonstrated elevated levels of a myriad of pro-inflammatory cytokines in users versus non-users. Differences in signaling cascades of activated T cells between users and non-users were also observed. A number of anti-inflammatory cytokines were inversely correlated with serum phytocannabinoids. These results suggest that cannabis exposure, which can desensitize cannabinoid receptors, may prime pro-inflammatory pathways in pediatric IBD patients., Competing Interests: Conflict of Interest No conflict of interest exist regarding this manuscript

The heat shock response is a critical component of the inflammatory cascade that prevents misfolding of new proteins and regulates immune responses. Activation of clusters of differentiation (CD)4 + T cells causes an upregulation of heat shock transcription factor, heat shock factor 1 (HSF1). We hypothesized that HSF1 promotes a pro-regulatory phenotype during inflammation. To validate this hypothesis, we interrogated cell-specific HSF1 knockout mice and HSF1 transgenic mice using in vitro and in vivo techniques. We determined that while HSF1 expression was induced by anti-CD3 stimulation alone, the combination of anti-CD3 and transforming growth factor β, a vital cytokine for regulatory T cell (Treg) development, resulted in increased activating phosphorylation of HSF1, leading to increased nuclear translocation and binding to heat shock response elements. Using chromatin immunoprecipitation (ChIP), we demonstrate the direct binding of HSF1 to foxp3 in isolated murine CD4 + T cells, which in turn coincided with induction of FoxP3 expression. We defined that conditional knockout of HSF1 decreased development and function of Tregs and overexpression of HSF1 led to increased expression of FoxP3 along with enhanced Treg suppressive function. Adoptive transfer of CD45RB High CD4 colitogenic T cells along with HSF1 transgenic CD25 + Tregs prevented intestinal inflammation when wild-type Tregs did not. Finally, overexpression of HSF1 provided enhanced barrier function and protection from murine ileitis. This study demonstrates that HSF1 promotes Treg development and function and may represent both a crucial step in the development of induced regulatory T cells and an exciting target for the treatment of inflammatory diseases with a regulatory T-cell component. SIGNIFICANCE STATEMENT: The heat shock response (HSR) is a canonical stress response triggered by a multitude of stressors, including inflammation. Evidence supports the role of the HSR in regulating inflammation, yet there is a paucity of data on its influence in T cells specifically. Gut homeostasis reflects a balance between regulatory clusters of differentiation (CD)4 + T cells and pro-inflammatory T-helper (Th)17 cells. We show that upon activation within T cells, heat shock factor 1 (HSF1) translocates to the nucleus, and stimulates Treg-specific gene expression. HSF1 deficiency hinders Treg development and function and conversely, HSF1 overexpression enhances Treg development and function. While this work, focuses on HSF1 as a novel therapeutic target for intestinal inflammation, the findings have significance for a broad range of inflammatory conditions., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To identify types, evidence, and study gaps of alternative HIV preexposure prophylaxis (PrEP) care delivery models in the published literature., Design: Systematic review and narrative synthesis., Methods: We searched in the US Centers for Disease Control and Prevention (CDC) Prevention Research Synthesis (PRS) database through December 2022 (PROSPERO CRD42022311747). We included studies published in English that reported implementation of alternative PrEP care delivery models. Two reviewers independently reviewed the full text and extracted data by using standard forms. Risk of bias was assessed using the adapted Newcastle-Ottawa Quality Assessment Scale. Those that met our study criteria were evaluated for efficacy against CDC Evidence-Based Intervention (EBI) or Evidence-Informed Intervention (EI) criteria or Health Resources and Services Administration Emergency Strategy (ES) criteria, or for applicability by using an assessment based on the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework., Results: This review identified 16 studies published between 2018 and 2022 that implemented alternative prescriber ( n  = 8), alternative setting for care ( n  = 4), alternative setting for laboratory screening ( n  = 1), or a combination of the above ( n  = 3) . The majority of studies were US-based ( n  = 12) with low risk of bias ( n  = 11). None of the identified studies met EBI, EI, or ES criteria. Promising applicability was found for pharmacists prescribers, telePrEP, and mail-in testing., Conclusions: Delivery of PrEP services outside of the traditional care system by expanding providers of PrEP care (e.g. pharmacist prescribers), as well as the settings of PrEP care (i.e. telePrEP) and laboratory screening (i.e. mail-in testing) may increase PrEP access and care delivery., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Up to 50% of those diagnosed with HIV in the U.S. are not retained in medical care. Care retention provides opportunity to monitor benefits of HIV therapy and enable viral suppression. To increase retention, there is a need to prioritize best practices appropriate for translation and dissemination for real-world implementation. Eighteen interventions from CDC's Compendium of Evidence-Based Interventions were scored using the RE-AIM framework to determine those most suitable for dissemination. A CDC Division of HIV Prevention workgroup developed a RE-AIM scale with emphasis on the Implementation and Maintenance dimensions and less emphasis on the Efficacy dimension since all 18 interventions were already identified as evidence-based or evidence-informed. Raters referenced primary efficacy publications and scores were averaged for a ranked RE-AIM score for interventions. Of 18 interventions, four included care linkage and 7 included viral suppression outcomes. Interventions received between 20.6 and 35.3 points (45 maximum). Scores were converted into a percentage of the total possible with ranges between 45.8 and 78.4%. Top four interventions were ARTAS (78.4%); Routine Screening for HIV (RUSH) (73.2%); Optn4Life (67.4%) and Virology Fast Track (65.9%). All four scored high on Implementation and Maintenance dimensions. Select items within the scale were applicable to health equity, covering topics such as reaching under-served focus populations and acceptability to that population. Navigation-enhanced Case Management (NAV) scored highest on the health equity subscale. RE-AIM prioritization scores will inform dissemination and translation efforts, help clinical staff select feasible interventions for implementation, and support sustainability for those interventions., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The majority of biological processes are regulated by enzymes, precise control over specific enzymes could create the potential for controlling cellular processes remotely. We show that the thermophilic enzyme thermolysin can be remotely activated in 17.76 MHz radiofrequency (RF) fields when covalently attached to 6.1 nm gold coated magnetite nanoparticles. Without raising the bulk solution temperature, we observe enzyme activity as if the solution was 16 ± 2 °C warmer in RF fields-an increase in enzymatic rate of 129 ± 8%. Kinetics studies show that the activity increase of the enzyme is consistent with the induced fit of a hot enzyme with cold substrate.

Background: The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. Some MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC, is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here we tested the expression and functional role of MUC5AC/Muc5ac in UC biopsies and murine colitis., Methods: We measured MUC5AC/Muc5ac expression in UC biopsies and in dextran sulfate sodium (DSS) colitis. We performed DSS colitis in mice deficient in Muc5ac (Muc5ac-/-) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial-epithelial interaction and translocation to mesenteric lymph nodes. Antibiotic treatment and 16S rRNA gene sequencing were performed to directly investigate the role of bacteria in murine colitis., Results: Colonic MUC5AC/Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac-/- mice experienced worsened injury and inflammation in DSS colitis compared with control mice. This result was associated with increased bacterial-epithelial contact and translocation to the mesenteric lymph nodes. However, no change in microbial abundance or community composition was noted. Antibiotic treatment normalized colitis severity in Muc5ac-/- mice to that of antibiotic-treated control mice., Conclusions: MUC5AC/Muc5ac induction in the acutely inflamed colon controls injury by reducing bacterial breach of the MGL., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

This paper describes the development of a formula to determine which evidence-based behavioral interventions (EBIs) targeting HIV-negative persons would be cost-saving in comparison to the lifetime cost of HIV treatment and the process by which this formula was used to prioritize those with greatest potential impact for continued dissemination. We developed a prevention benefit index (PBI) to rank risk-reduction EBIs for HIV-negative persons based on their estimated cost for achieving the behavior change per one would-be incident infection of HIV. Inputs for calculating the PBI included the mean estimated cost-per-client served, EBI effect size for the behavior change, and the HIV incidence per 100,000 persons in the target population. EBIs for which the PBI was ≤ $402,000, the estimated lifetime cost of HIV care, were considered cost-saving. We were able to calculate a PBI for 35 EBI and target population combinations. Ten EBIs were cost-saving having a PBI below $402,000. One EBI did not move forward for dissemination due to high start-up dissemination costs. DHAP now supports the dissemination of 9 unique EBIs targeting 13 populations of HIV-negative persons. The application of a process, such as the PBI, may assist other health-field policymakers when making decisions about how to select and fund implementation of EBIs.

Pro-inflammatory cytokine TNFα antagonizes regulatory T cell (Treg) suppressive function with a measurable reduction of IL-10 protein secretion. Tregs are critical to suppress excessive immune activation, particularly within the intestine where high antigenic loads elicit chronic subclinical immune activation. Employing a TNFα-driven murine inflammatory bowel disease (IBD) model (TNF ΔARE/+ ), which mirrors the Treg expansion and transmural ileitis seen in Crohn's disease, we demonstrate that the TNFα-mediated loss of Treg suppressive function coincides with induction of a specific miRNA, miR-106a in both humans and mice, via NFκB promoter binding to suppress post-transcriptional regulation of IL-10 release. Elevation of miR-106a and impaired Treg function in this model recapitulate clinical data from IBD patients. MiR-106a deficiency promotes Treg induction, suppressive function and IL-10 production in vitro. MiR-106a knockout attenuated chronic murine ileitis, whereas T cell restricted deficiency of miR-106a attenuated adoptive transfer colitis. In both models, attenuated inflammation coincided with suppression of both Th1 and Th17 cell subset expansion within the intestinal lamina propria. Collectively, our data demonstrate impaired Treg suppressive function in a murine IBD model consistent with human disease and support the potential for inhibition of miR-106a as a future therapeutic approach to treat chronic inflammatory conditions including IBD.

Background and Aims: Inflammatory Bowel Diseases [IBDs] are chronic intestinal inflammatory conditions in part mediated by CD4+ T cells. Anti-inflammatory Foxp3+ regulatory T cells [Tregs] maintain immune homeostasis and protect against IBD development via multiple mechanisms, including cytokine secretion and cell-cell interaction. CCAAT enhancer binding protein-beta [C/EBPβ] is a stress-responsive transcription factor linked with IBD susceptibility. Whole-body C/EBPβ deficiency induces CD4+ T cell-predominant hyperproliferation, and we hypothesize that this may be due to impaired Treg function., Methods: We used the C/EBPβ-/- mice in the CD45RBHigh adoptive transfer model, to assess C/EBPβ-/- CD4+ T cells for their colitiogenic potential, and C/EBPβ-/- CD4+ Foxp3+ Tregs for their ability to inhibit colitis. We assessed Tregs from the C/EBPβ-/- mice for expression of Treg functional genes and proteins., Results: Naïve C/EBPβ-/- CD4+ T cells are more colitogenic in vivo. The exacerbated colitis does not appear to reflect impaired Treg development, however, as C/EBPβ-/- mice displayed more, rather than fewer intestinal CD4+Foxp3+ Tregs in vivo. Instead, this reflects impaired Treg function as seen by the reduced capacity to suppress T cell proliferation in vitro, along with decreased secretion of the anti-inflammatory cytokine IL-10. These findings were corroborated in vivo by additional adoptive co-transfer studies in which wildtype Tregs prevented colitis but C/EBPβ-/- Tregs did not., Conclusion: C/EBPβ deficiency impairs Treg function and potentiates T cell-mediated colitis. A clearer understanding of the function of this transcription factor may provide a novel therapeutic strategy for IBD.

Intestinal epithelial barrier repair is vital for remission in inflammatory bowel disease (IBD). Extracellular adenosine signaling has been implicated in promoting restoration of epithelial barrier function. Currently, no clinically approved agents target this pathway. Adenosine signaling is terminated by uptake from the extracellular space via equilibrative nucleoside transporters (ENTs). We hypothesized that ENT inhibition could dampen intestinal inflammation. Initial studies demonstrated transcriptional repression of ENT1 and ENT2 in IBD biopsies or in murine IBD models. Subsequent studies in mice with global Ent1 or Ent2 deletion revealed selective protection of Ent2-/- mice. Elevated intestinal adenosine levels in conjunction with abolished protection following pharmacologic blockade of A2B adenosine receptors implicate adenosine signaling as the mechanism of gut protection in Ent2-/- mice. Additional studies in mice with tissue-specific deletion of Ent2 uncovered epithelial Ent2 as the target. Moreover, intestinal protection provided by a selective Ent2 inhibitor was abolished in mice with epithelium-specific deletion of Ent2 or the A2B adenosine receptor. Taken together, these findings indicate that increased mucosal A2B signaling following repression or deletion of epithelial Ent2 coordinates the resolution of intestinal inflammation. This study suggests the presence of a targetable purinergic network within the intestinal epithelium designed to limit tissue inflammation.

Gold nanoparticles in radiofrequency (RF) fields have been observed to heat. There is some debate over the mechanism of heating. Au 25 (SR) 18 in RF is studied for the mechanistic insights obtainable from precise synthetic control over exact charge, size, and spin for this nanoparticle. An electrophoretic mechanism can adequately account for the observed heat. This study adds a new level of understanding to gold particle heating experiments, allowing for the first time a conclusive connection between theoretical and experimentally observed heating rates.

Background and Aims: Cannabinoid receptor stimulation may have positive symptomatic effects on inflammatory bowel disease [IBD] patients through analgesic and anti-inflammatory effects. The cannabinoid 2 receptor [CB2R] is expressed primarily on immune cells, including CD4+ T cells, and is induced by active inflammation in both humans and mice. We therefore investigated the effect of targeting CB2R in a preclinical IBD model., Methods: Employing a chronic ileitis model [TNFΔARE/+ mice], we assessed expression of the CB2R receptor in ileal tissue and on CD4+ T cells and evaluated the effect of stimulation with CB2R-selective ligand GP-1a both in vitro and in vivo. Additionally, we compared cannabinoid receptor expression in the ilea and colons of healthy human controls with that of Crohn's disease patients., Results: Ileal expression of CB2R and the endocannabinoid anandamide [AEA] was increased in actively inflamed TNF∆ARE/+ mice compared with controls. CB2R mRNA was preferentially induced on regulatory T cells [Tregs] compared with T effector cells, approximately 2.4-fold in wild-type [WT] and 11-fold in TNF∆ARE/+ mice. Furthermore, GP-1a enhanced Treg suppressive function with a concomitant increase in IL-10 secretion. GP-1a attenuated murine ileitis, as demonstrated by improved histological scoring and decreased inflammatory cytokine expression. Lastly, CB2R is downregulated in both chronically inflamed TNF∆ARE/+ mice and in IBD patients., Conclusions: In summary, the endocannabinoid system is induced in murine ileitis but is downregulated in chronic murine and human intestinal inflammation, and CB2R activation attenuates murine ileitis, establishing an anti-inflammatory role of the endocannabinoid system., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

The Centers for Disease Control and Prevention provides trainings to support implementation of five evidence-based HIV prevention interventions (EBIs) for men who have sex with men (MSM): d-up: Defend Yourself!; Many Men, Many Voices; Mpowerment; Personalized Cognitive Counseling; and Popular Opinion Leader. We evaluated trainees' implementation of these EBIs and, using multivariable logistic regression, examined factors associated with implementation. Approximately 43% of trainees had implemented the EBIs for which they received training. Implementation was associated with working in community-based organizations (vs. health departments or other settings); acquiring training for Mpowerment or Popular Opinion Leader (vs. Personalized Cognitive Counseling); having ≥3 funding sources (vs. one); and having (vs. not having) sufficient time and necessary EBI resources. Findings suggest that implementation may vary by trainee characteristics, especially those related to employment setting, EBI training, funding, and perceived implementation barriers. Efforts that address these factors may help to improve EBI implementation among trainees.

Background and Aims: Inflammatory bowel disease [IBD] is characterised by a disruption of immune homeostasis, which is tightly regulated to protect against harmful pathogens yet not react to commensal antigens. Animal studies indicate that regulatory T cells [Treg] modulate the immune response to prevent IBD development. Lactoferrin [LF] is an endogenous anti-inflammatory pleiotropic protein secreted at high concentrations in colostrum and at mucosal sites. However, the effect of LF on specific T lymphocyte populations has not been studied. Here, we identify a novel mechanism by which a recombinant human LF, VEN-120, regulates T cell populations in health and disease., Methods: Two murine models of intestinal inflammation, the dextran sodium sulphate colitis model and the TNFΔARE/+ model of ileitis, were used to study the anti-inflammatory and T cell modulating ability of VEN-120. Flow cytometry was used to evaluate T cell populations within the lamina propria and mesenteric lymph nodes, and to evaluate the effect of VEN-120 on CD4+ T cells in vitro., Results: VEN-120 reduced inflammation in both models of IBD, accompanied by increased Tregs in the intestinal lamina propria. Treatment of CD4+ T cells in vitro resulted in an upregulation of Treg genes and skewing towards a Treg population. This in vitro T cell skewing translated to an increase of Treg homing to the intestinal lamina propria and associated lymph tissue in healthy mice., Conclusions: These data provide a novel immunological mechanism by which VEN-120 modulates T cells to restrict inflammatory T cell-driven disease., (© European Crohn’s and Colitis Organisation (ECCO) 2017.)

Background: Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear., Methods: This review reflects our current understanding of how targeting the endocannabinoid system, including cannabinoid receptors 1 and 2, endogenous cannabinoids anandamide and 2-arachidonoylglycerol, atypical cannabinoids, and degrading enzymes including fatty acid amide hydrolase and monoacylglycerol lipase, impacts murine colitis. In addition, the impact of cannabinoids on the human immune system is summarized., Results: Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression., Conclusions: Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD.

Superatom electron shell and/or geometric shell filling underlies the thermodynamic stability of coinage and alkali metal clusters in both theoretical and experimental results. Factors beyond simple shell filling contribute substantially to the lifetime of ligated clusters in solution. Such factors include the nature of the solvent, the atmosphere and the steric size of the ligand shell. Here we systematically lay out a 'practical' stability model for ligated metal clusters, which includes both shell-closing aspects and colloidal stability aspects. Cluster decomposition may follow either fusion or fission pathways. Solvent polarity can be determinative of the decomposition pathway.

Partnership for Health (PfH) is an evidence-based, clinician-delivered HIV prevention program conducted in the United States for HIV-positive patients. This intervention strives to reduce risky sexual behaviors through provider-patient discussions on safer sex and HIV status disclosure. A cross-sectional, mixed-methods design was used to evaluate the dissemination and implementation of PfH, including training evaluations, an online trainee survey, and interviews with national trainers for PfH. Descriptive statistics were calculated with the categorical data, whereas thematic analysis was completed with the qualitative data. Between 2007 and 2013, PfH was disseminated to 776 individuals from 104 different organizations in 21 states/territories. The smallest proportion of trainees was physicians (6.9%). More than three-fourths of survey respondents (78.6%) reported using PfH, but less than one-third (31.8%) used the intervention with every patient. The PfH training supports the implementation of the intervention; however, challenges were experienced in clinician engagement. Tailored strategies to recruit and train clinicians providing care to HIV-positive patients are required.

Zwitterionic capsular polysaccharides (ZPSs) are bacterial products that modulate T cells, including inducing anti-inflammatory IL-10-secreting T regulatory cells (Tregs). However, only a few diverse bacteria are known to modulate the host immune system via ZPS. We present a genomic screen for bacteria encoding ZPS molecules. We identify diverse host-associated bacteria, including commensals and pathogens with known anti-inflammatory properties, with the capacity to produce ZPSs. Human mononuclear cells stimulated with lysates from putative ZPS-producing bacteria induce significantly greater IL-10 production and higher proportions of Tregs than lysates from non-ZPS-encoding relatives or a commensal strain of Bacteroides cellulosilyticus in which a putative ZPS biosynthetic operon was genetically disrupted. Similarly, wild-type B. cellulosilyticus DSM 14838, but not a close relative lacking a putative ZPS, attenuated experimental colitis in mice. Collectively, this screen identifies bacterial strains that may use ZPSs to interact with the host as well as those with potential probiotic properties., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In 1999, IOM issued a report that recommended that the Centers for Disease Control and Prevention should disseminate evidence-based HIV prevention interventions (EBIs) to be implemented by health departments, community-based organizations, drug treatment centers, and clinics. Based on these recommendations, the Diffusion of Effective Behavioral Interventions Project was initiated in 2000 and began disseminating interventions into public health practice. For 15 years, the Centers for Disease Control and Prevention has disseminated 29 EBIs to more than 11,300 agencies. Lessons were identified during the 15 years of implementation regarding successful methods of dissemination of EBIs. Lessons around selecting interventions for dissemination, developing a dissemination infrastructure including a resource website (https://effectiveinterventions.cdc.gov), and engagement with stakeholders are discussed. A continuous development approach ensured that intervention implementation materials, instructions, and technical assistance were all tailored to the needs of end users, focus populations, and agency capacities. Six follow-up studies demonstrated that adopters of EBIs were able to obtain comparable outcomes to those of the original efficacy research. The Diffusion of Effective Behavioral Interventions Project may offer guidance for other large, national, evidence-based public health dissemination projects., (Published by Elsevier Inc.)

γδ T lymphocytes are a unique T cell population with important anti-inflammatory capabilities. Their role in acute lung injury, however, is poorly understood but may provide significant insight into lung-protective mechanisms occurring after injury. In a murine model of lung injury, wild-type C57BL/6 and TCRδ(-/-) mice were exposed to Escherichia coli LPS, followed by analysis of γδ T cell and macrophage subsets. In the absence of γδ T cells, TCRδ(-/-) mice developed increased inflammation and alveolar-capillary leak compared with wild-type C57BL/6 mice after LPS exposure that correlated with expansion of distinct macrophage populations. Classically activated M1 macrophages were increased in the lung of TCRδ(-/-) mice at d 1, 4, and 7 after LPS exposure that peaked at d 4 and persisted at d 7 compared with wild-type animals. In response to LPS, Vγ1 and Vγ7 γδ T cells were expanded in the lung and expressed IL-4. Coculture experiments showed decreased expression of TNF-α by resident alveolar macrophages in the presence of γδ T cells that was reversed in the presence of an anti-IL-4-blocking antibody. Treatment of mice with rIL4 resulted in reduced numbers of M1 macrophages, inflammation, and alveolar-capillary leak. Therefore, one mechanism by which Vγ1 and Vγ7 γδ T cells protect against LPS-induced lung injury is through IL-4 expression, which decreases TNF-α production by resident alveolar macrophages, thus reducing accumulation of M1 macrophages, inflammation, and alveolar-capillary leak., (© Society for Leukocyte Biology.)

Central to inflammatory bowel disease (IBD) pathogenesis is loss of mucosal barrier function. Emerging evidence implicates extracellular adenosine signaling in attenuating mucosal inflammation. We hypothesized that adenosine-mediated protection from intestinal barrier dysfunction involves tissue-specific signaling through the A2B adenosine receptor (Adora2b) at the intestinal mucosal surface. To address this hypothesis, we combined pharmacologic studies and studies in mice with global or tissue-specific deletion of the Adora2b receptor. Adora2b(-/-) mice experienced a significantly heightened severity of colitis, associated with a more acute onset of disease and loss of intestinal epithelial barrier function. Comparison of mice with Adora2b deletion on vascular endothelial cells (Adora2b(fl/fl)VeCadCre(+)) or intestinal epithelia (Adora2b(fl/fl)VillinCre(+)) revealed a selective role for epithelial Adora2b signaling in attenuating colonic inflammation. In vitro studies with Adora2b knockdown in intestinal epithelial cultures or pharmacologic studies highlighted Adora2b-driven phosphorylation of vasodilator-stimulated phosphoprotein (VASP) as a specific barrier repair response. Similarly, in vivo studies in genetic mouse models or treatment studies with an Adora2b agonist (BAY 60-6583) recapitulate these findings. Taken together, our results suggest that intestinal epithelial Adora2b signaling provides protection during intestinal inflammation via enhancing mucosal barrier responses.

MicroRNAs (miRNAs) are endogenous oligoribonucleotides with exciting therapeutic potential. Early studies established a clear role for miRNAs in leukocyte biology. The first miRNA-based therapy, miravirsen, is now in phase 2 clinical trials, making the reality of these therapies undeniable. The capacity for miRNAs to fine-tune inflammatory signaling make them attractive treatment targets for immunological diseases. Nonetheless, the degree of redundancy among miRNAs, coupled with the promiscuity of miRNA binding sites in the transcriptome, require consideration when designing miRNA-directed interventions. Altered miRNA expression occurs across a range of inflammatory conditions, including inflammatory bowel disease, arthritis, and diabetes. However, very few studies successfully treated murine models of immunological diseases with miRNA-based approaches. While discussing recent studies targeting miRNAs to treat immunological conditions, we also reflect on the risks of miRNA targeting and showcase some newer delivery systems that may improve the pharmacological profile of this class of therapeutics., (Copyright © 2015 by The American Association of Immunologists, Inc.)

The regulation of T cell and DC retention and lymphatic egress within and from the intestine is critical for intestinal immunosurveillance; however, the cellular processes that orchestrate this balance during IBD remain poorly defined. With the use of a mouse model of TNF-driven Crohn's-like ileitis (TNF(Δ) (ARE)), we examined the role of CCR7 in the control of intestinal T cell and DC retention/egress during experimental CD. We observed that the frequency of CCR7-expressing TH1/TH17 effector lymphocytes increased during active disease in TNF(Δ) (ARE) mice and that ΔARE/CCR7(-/-) mice developed exacerbated ileitis and multiorgan inflammation, with a marked polarization and ileal retention of TH1 effector CD4(+) T cells. Furthermore, adoptive transfer of ΔARE/CCR7(-/-) effector CD4(+) into lymphopenic hosts resulted in ileo-colitis, whereas those transferred with ΔARE/CCR7(+/+) CD4(+) T cells developed ileitis. ΔARE/CCR7(-/-) mice had an acellular draining MLN, decreased CD103(+) DC, and decreased expression of RALDH enzymes and of CD4(+)CD25(+)FoxP3(+) Tregs. Lastly, a mAb against CCR7 exacerbated ileitis in TNF(Δ) (ARE) mice, phenocopying the effects of congenital CCR7 deficiency. Our data underscore a critical role for the lymphoid chemokine receptor CCR7 in orchestrating immune cell traffic and TH1 versus TH17 bias during chronic murine ileitis., (© Society for Leukocyte Biology.)

When seeking to prevent HIV/AIDS in women, attending to aspects of their lived experience provides opportunities to address the presence of social determinants in prevention strategies. According to the CDC, in 2010, the rate of new HIV infections among Black women was 20 times that of White women, while among Hispanic/Latino women it was 4 times the rate of White women. Additionally, 86% of HIV infections in women were attributed to heterosexual contact and 14% to injection drug use. The WHO indicates that worldwide, 49% of individuals infected by HIV are women, with a predominant source of infection tied to heterosexual transmission. This paper presents social determinants as influential factors in terms of women's sexual behavior decision-making, along with suggested structural interventions to address the social determinants of their HIV risks. Secondary analysis was conducted on data from an earlier study (Abdul-Quader and Collins, 2011) which used concept-mapping to examine the feasibility, evaluability, and sustainability of structural interventions for HIV prevention. The current analysis focused on structural interventions applicable to women and their HIV prevention needs. Three themes emerged: economic interventions, responses to violence against women, and integrated health service delivery strategies. The themes provide a foundation for next steps regarding research, policy planning, and intervention implementation that is inclusive of women's lived experience. The paper concludes with suggestions such as attention to innovative projects and a paradigm shift regarding policy planning as key next steps towards HIV prevention that reflects the contextual complexity of women's lived experiences.

This feature article reviews the thermal dissipation of nanoscopic gold under radiofrequency (RF) irradiation. It also presents previously unpublished data addressing obscure aspects of this phenomenon. While applications in biology motivated initial investigation of RF heating of gold nanoparticles, recent controversy concerning whether thermal effects can be attributed to nanoscopic gold highlight the need to understand the involved mechanism or mechanisms of heating. Both the nature of the particle and the nature of the RF field influence heating. Aspects of nanoparticle chemistry which may affect thermal dissipation include the hydrodynamic diameter of the particle, the oxidation state and related magnetism of the core, and the chemical nature of the ligand shell. Aspects of RF which may affect thermal dissipation include power, frequency and antenna designs that emphasize relative strength of magnetic or electric fields. These nanoparticle and RF properties are analysed in the context of three heating mechanisms proposed to explain gold nanoparticle heating in an RF field. This article also makes a critical analysis of the existing literature in the context of the nanoparticle preparations, RF structure, and suggested mechanisms in previously reported experiments.

Inflammatory bowel diseases are chronic intestinal inflammatory diseases thought to reflect a dysregulated immune response. Although antibody-based inhibition of tumor necrosis factor-α (TNF-α) has provided relief to many inflammatory bowel diseases patients, these therapies are either ineffective in a patient subset or lose their efficacy over time, leaving an unmet need for alternatives. Given the critical role of the heat shock response in regulating inflammation, this study proposed to define the impact of selective inhibition of heat shock protein 90 (HSP90) on intestinal inflammation. Using multiple preclinical mouse models of inflammatory bowel diseases, we demonstrate a potent anti-inflammatory effect of selective inhibition of the HSP90 C-terminal ATPase using the compound novobiocin. Novobiocin-attenuated dextran sulfate sodium-induced colitis and CD45RB adoptive-transfer colitis through the suppression of inflammatory cytokine secretion, including TNF-α. In vitro assays demonstrate that CD4 T cells treated with novobiocin produced significantly less TNF-α measured by intracellular cytokine staining and by enzyme-linked immunosorbent assay. This corresponded to significantly decreased nuclear p65 translocation by Western blot and a decrease in nuclear factor-κB luciferase activity in Jurkat T cells. Finally, to verify the anti-TNF action of novobiocin, 20-week-old TNFΔ mice were treated for 2 weeks with subcutaneous administration of novobiocin. This model has high levels of circulating TNF-α and exhibits spontaneous transmural segmental ileitis. Novobiocin treatment significantly reduced inflammatory cell infiltrate in the ileal lamina propria. HSP90 inhibition with novobiocin offers a novel method of inflammatory cytokine suppression without potential for the development of tolerance that limits current antibody-based methods.

Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-γ in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-γ and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-γ was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific IL-10R1-null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-γ.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition thought to reflect a failure of the enteral immune system to adequately regulate itself. Inflammatory stress drives upregulation of heat-shock proteins (HSPs), including the pro-inflammatory chaperone, HSP90. This protein sequesters the transcription factor, heat-shock factor 1 (HSF1) in the cytoplasm preventing transcription of a number of anti-inflammatory proteins. We hypothesized that inhibition of HSP90 would exert an anti-inflammatory effect and thereby attenuate intestinal inflammation in murine models of IBD. Inhibition of HSP90 with 17-allylaminogeldanamycin (17-AAG) reduced inflammation in acute dextran sodium sulfate and chronic CD45RB(High) colitis models coinciding with increased interleukin (IL)-10 production in the colon. Regulatory T cells (Tregs) from mice treated with 17-AAG demonstrated significantly greater suppressive capacity in vitro abolished in HSF1-/- or IL-10-/- cells. Finally, Tregs treated with 17-AAG exhibited increased nuclear localization of HSF1 with resultant upregulation of HSF1 response genes, including HSP70, HSP90 and IL-10.

Background: Fecal alpha-1-antitrypsin (AAT) clearance has been a marker of clinical disease severity in inflammatory bowel diseases (IBDs) for many years. Although AAT deficiency is more often associated with lung and liver pathologies, AAT-deficient patients with concomitant IBD have been shown to develop more aggressive disease and rapid progression to surgery. Although recent studies have highlighted the pleiotropic anti-inflammatory functions of AAT, including reducing proinflammatory cytokine production and suppressing immune cell activation, its potential therapeutic role in IBD has not been described., Methods: The therapeutic potential of human AAT administration was assessed in murine models of IBD including new-onset and established chemically induced colitis and spontaneous chronic murine ileitis. Histological assessment of inflammation, cytokine secretion profiling, and flow cytometric evaluation of inflammatory infiltrate were performed in each model. The effect of AAT on intestinal barrier function was also examined both in vitro and in vivo., Results: AAT attenuated inflammation in small and large intestinal IBD models through reduced secretion of proinflammatory cytokines, inflammatory cell infiltration, and reduced tissue injury. AAT also increased intestinal restitution after chemically induced colitis. AAT significantly decreased intestinal permeability in vitro and in vivo as part of a protective mechanism for both acute and chronic models of IBD., Conclusions: Our findings describe a beneficial role for AAT in IBD models through suppression of cytokine production and enhanced intestinal barrier function. This raises the possibility that AAT supplementation, which has a long history of proven safety, may have a therapeutic effect in human IBD.

The intestinal epithelium is a dynamic barrier playing an active role in intestinal homeostasis and inflammation. Intestinal barrier function is dysregulated during inflammatory bowel disease (IBD), with epithelial cells playing a significant part in generating an inflammatory milieu through the release of signals that attract leukocytes to the intestinal lamina propria. However, it is increasingly appreciated that the intestinal epithelium mediates a counterbalancing response to drive resolution. Drawing analogies with neuronal development, where the balance of chemoattractive and chemorepellent signals is key to directed neuronal movement it has been postulated that such secreted cues play a role in leukocyte migration. Netrin-1 is one of the best-described neuronal guidance molecules, which has been shown to play a significant role in directed migration of leukocytes. Prior to our study the potential role of netrin-1 in IBD was poorly characterized. We defined netrin-1 as an intestinal epithelial-derived protein capable of limiting neutrophil recruitment to attenuate acute colitis. Our study highlights that the intestinal epithelium releases factors during acute inflammation that are responsible for fine-tuning the immune response. Exploration of these epithelial-mediated protective mechanisms will shed light on the complexity of the intestinal epithelial barrier in health and disease.

Background: The earliest endoscopically-evident lesion in Crohn's disease is the aphthous ulcer, which develops over ectopic lymphoid tissues (ie, inducible lymphoid follicles (ILF), tertiary lymphoid tissue (TLT)) in the chronically inflamed intestine. ILF/TLT are induced within effector sites by homeostatic lymphoid chemokines, but their role in the development of intestinal ILF/TLT and in the pathogenesis of Crohn's disease is poorly understood., Design: Using a mouse model of Crohn's-like ileitis (TNFARE) which develops florid induction of ILF/TLT within its terminal ileum, the contribution of the CCR7/CCL19/CCL21 chemokine axis during the development of TLT and its role in disease pathogenesis were assessed., Results: Both CCL19 and CCL21 were increased within the inflamed ileum of TNFARE mice, which resulted in CCR7 internalisation and impaired T cell chemotaxis. ILF/TLT were a major source of CCL19 and CCL21 and increased local synthesis, augmented recruitment/retention of effector, naïve and central memory T cell subsets within the inflamed ileum. Immunoblockade of CCR7 resulted in further effector T cell retention and exacerbation of ileitis., Conclusions: Induction of ILF/TLT in the chronically inflamed intestine alters the homeostatic CCL19-CCL21 lymphoid-chemokine gradient and increases recruitment/retention of effector CCR7+ T cell subsets within the terminal ileum, contributing to the perpetuation of chronic inflammation. Thus, blockade of CCR7 or its ligands might result in deleterious consequences for subjects with chronic inflammatory diseases.

Translating evidence-based HIV/STD prevention interventions and research findings into applicable HIV prevention practice has become an important challenge for the fields of community psychology and public health due to evidence-based interventions and evidence-based practice being given higher priority and endorsement by federal, state, and local health department funders. The Interactive Systems Framework (ISF) for Dissemination and Implementation and the Division of HIV/AIDS Prevention (DHAP) Research-to-Practice model both address this challenge. The DHAP model and the ISF are each presented with a brief history and an introduction of their features from synthesis of research findings through translation into intervention materials to implementation by prevention providers. This paper describes why the ISF and the DHAP model were developed and the similarities and differences between them. Specific examples of the use of the models to translate research to practice and the subsequent implications for support of each model are provided. The paper concludes that the ISF and the DHAP model are truly complementary with some unique differences, while both contribute substantially to addressing the gap between identifying effective programs and ensuring their widespread adoption in the field.

As dietary supplementation with β-glucans can stimulate the innate immune response in the porcine gastrointestinal system (GIT), the aim of this study was to determine if the effects of β-glucan supplementation extend beyond the GIT to systemic levels. Hence, the effects of dietary supplementation of β-glucans derived from Laminara digitata, Laminara hyperborea, and Sacharomyces cerevisiae on cytokine expression in the porcine liver with or without ex vivo lipopolysaccharide (LPS) challenge were examined. No significant differences in gene expression were observed in the unchallenged liver tissue, but differences were observed in all supplementation groups in the LPS challenged tissue. Relative to the basal diet, IL-6 (P < 0.05) was less expressed in the S. cerevisiae supplementation group, IL-6 (P < 0.05) and TLR-4 (P < 0.05) were less expressed in the L. digitata supplementation group, and IL-10 (P = 0.06) and IL-1α (P = 0.02) were more expressed in the L. hyperborea supplementation group. There was a ≈ 3-fold increase in both IL-10 and IL-1α in the liver samples of L. hyperborea relative to the L. digitata supplementation groups (P < 0.01). The results indicate that supplementation with β-glucans from both yeast and seaweed sources have systemic effects evidenced by changes in cytokine expression in the liver in response to LPS challenge; however, the cytokines affected varied according to the source of the β-glucan.

An unregulated T(h)17 inflammatory response has been highlighted as a major contributor to the underlying pathology of inflammatory bowel diseases (IBD) whereas regulatory T (T(REG)) cells) have been highlighted as pivotal in suppressing autoimmune and inflammatory responses in the gut. Following dietary supplementation, β-glucans have been shown to reduce the T(h)17 signature molecule IL-17a in the porcine colon. To expand this observation we examined the effects of supplementing feeds with β-glucans derived from seaweeds Laminaria hyperborea and Laminaria digitata and the yeast Saccharomyces cerevisiae on gene expression of a range of cytokines, receptors, and signal transducing molecules relevant to the T(h)17 and T(REG) pathways in the porcine colon. All sources of β-glucans significantly decreased the expression of T(h)17-related cytokines (IL-17a, IL-17F, and IL-22), receptor IL23R, and IL-6. There was no alteration to the T(REG)-related target, Foxp3, or to TGF-β, although a significant reduction in IL-10 was observed in the L. digitata supplementation group.

β-Glucans have been identified as natural biomolecules with immunomodulatory activity. The first objective of the present study was to compare the effects of purified β-glucans derived from Laminaria digitata, L. hyperborea and Saccharomyces cerevisiae on piglet performance, selected bacterial populations and intestinal volatile fatty acid (VFA) production. The second aim was to compare the gene expression profiles of the markers of pro- and anti-inflammation in both unchallenged and lipopolysaccharide (LPS)-challenged ileal and colonic tissues. β-Glucans were included at 250 mg/kg in the diets. The β-glucans derived from L. hyperborea, L. digitata and S. cerevisiae all reduced the Enterobacteriaceae population (P<0·05) without influencing the lactobacilli and bifidobacteria populations (P>0·05) in the ileum and colon. There was a significant interaction between gastrointestinal region and β-glucan source in the expression of cytokine markers, IL-1α (<0·001), IL-10 (P<0·05), TNF-α (P<0·05) and IL-17A (P<0·001). β-Glucans did not stimulate any pro- or anti-inflammatory cytokine markers in the ileal epithelial cells. In contrast, the expression of a panel of pro- and anti-inflammatory cytokines (IL-1α, IL-10, TNF-α and IL-17A) was down-regulated in the colon following exposure to β-glucans from all the three sources. However, the data suggest that the soluble β-glucans derived from L. digitata may be acting via a different mechanism from the insoluble β-glucans derived from L. hyperborea and S. cerevisiae, as the VFA profile was different in the L. digitata-treated animals. There was an increase in IL-8 gene expression (P<0·05) in the gastrointestinal tract from the animals exposed to L. digitata following an LPS ex vivo challenge that was not evident in the other two treatment groups. In conclusion, β-glucans from both seaweed and yeast sources reduce Enterobacteriaceae counts and pro-inflammatory markers in the colon, though the mechanisms of action may be different between the soluble and insoluble fibre sources.

Unlabelled: BACKGROUND; Imprinting an effector or regulatory phenotype on naïve T cells requires education at induction sites by dendritic cells (DC). Objectives To analyse the effect of inflammation on the frequency of mononuclear phagocytes (MP) and the effect of altering their frequency by administration of Flt3-L in chronic ileitis., Methods: Using a tumour necrosis factor (TNF) driven model of ileitis (ie, TNFΔARE) that recapitulates many features of Crohn's disease (CD), dynamic changes in the frequency and functional state of MP within the inflamed ileum were assessed by flow cytometry, immunofluorescence and real-time reverse-transcription PCR and by generating CX(3)CR1 GFP-reporter TNFΔARE mice. The effect of Flt3-L supplementation on the severity of ileitis, and the frequency of CD103(+) DC and of FoxP3(+) regulatory T cells was also studied in TNFΔARE mice., Results: CD11c(Hi)/MHCII(+) MP accumulated in inflamed ilea, predominantly mediated by expansion of the CX(3)CR1(+) MP subpopulation. This coincided with a decreased pro-regulatory CD103(+) DC. The phenotype of these MP was that of activated cells, as they expressed increased CD80 and CD86 on their surface. Flt3-ligand administration resulted in a preferential expansion of CD103(+) DC that attenuated the severity of ileitis in 20-week-old TNFΔARE mice, mediated by increased CD4(+)/CD25(+)/FoxP3(+) regulatory T cells., Conclusions: Results support a role for Flt3-L as a potential therapeutic agent in Crohn's-like ileitis.

Background: Inflammatory bowel diseases, encompassing Crohn's disease and ulcerative colitis, are characterised by persistent leucocyte tissue infiltration leading to perpetuation of an inappropriate inflammatory cascade. The neuronal guidance molecule netrin-1 has recently been implicated in the orchestration of leucocyte trafficking during acute inflammation. We therefore hypothesised that netrin-1 could modulate leucocyte infiltration and disease activity in a model of inflammatory bowel disease., Design: DSS-colitis was performed in mice with partial genetic netrin-1 deficiency (Ntn-1(+/-) mice) or wild-type mice treated with exogenous netrin-1 via osmotic pump to examine the role of endogenous and therapeutically administered netrin-1. These studies were supported by in vitro models of transepithelial migration and intestinal epithelial barrier function., Results: Consistent with our hypothesis, we observed induction of netrin-1 during intestinal inflammation in vitro or in mice exposed to experimental colitis. Moreover, mice with partial netrin-1 deficiency demonstrated an exacerbated course of DSS-colitis compared to littermate controls, with enhanced weight loss and colonic shortening. Conversely, mice treated with exogenous mouse netrin-1 experienced attenuated disease severity. Importantly, permeability studies and quantitative assessment of apoptosis reveal that netrin-1 signalling events do not alter mucosal permeability or intestinal epithelial cell apoptosis. In vivo studies of leucocyte transmigration demonstrate suppression of neutrophil trafficking as a key function mediated by endogenous or exogenously administered netrin-1. Finally, genetic studies implicate the A2B adenosine receptor in netrin-1-mediated protection during DSS-colitis., Conclusions: The present study identifies a previously unrecognised role for netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking.

Background & Aims: Retinoic acid (RA), produced by intestinal epithelial cells (IECs) and dendritic cells (DCs) promotes the induction of regulatory T cells (Tregs) and decreases the induction of T-helper (Th)17 cells., Methods: We studied the roles of RA in mice that overproduce tumor necrosis factor (TNF) and develop chronic ileitis (TNF&#95;ARE mice). We assessed the frequency and function of CD103+ DCs, Th17 cells, and Tregs by flow cytometry, and we measured expression of cytokines and retinaldehyde dehydrogenase (RALDH) enzymes in ileum samples, DCs, and IECs by real-time polymerase chain reaction. We quantified RA by electrochemical analysis and examined the effect of RA supplementation on TNF-induced ileitis using histologic, coculture, and suppression assays and flow cytometry., Results: Numbers of CD103+ DCs decreased in the inflamed ilea of mice with chronic disease; RA synthetic machinery (RALDH1,2) was down-regulated. Nevertheless, the proportion of CD4+, CD25+, FoxP3+ Tregs increased, indicating an alternate source for RA. IECs responded to reduced levels of RA by up-regulating RALDH3 in vivo and in vitro. Net tissue levels of RA remained lower in TNF+ARE than wild-type mice, indicating that epithelial up-regulation of RALDH3 could not maintain adequate concentrations of RA, probably because of loss of IEC mass. RA supplementation significantly attenuated disease by increasing the number and function of CD103+ DCs and Tregs and reducing Th17 cells., Conclusions: Reduced levels of RA appear to induce IECs to up-regulate synthesis of RA. RA supplementation attenuates ileitis through its effects on CD103+ DCs, Tregs, and Th17 cells. RA supplementation might offer therapeutic benefit in Crohn's disease., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

IL-37, a newly described member of the IL-1 family, functions as a fundamental inhibitor of innate inflammation and immunity. In the present study, we examined a role for IL-37 during experimental colitis. A transgenic mouse strain was generated to express human IL-37 (hIL-37tg), and these mice were subjected to dextran sulfate sodium (DSS)-induced colitis. Despite the presence of a CMV promoter to drive expression of IL-37, mRNA transcripts were not present in colons at the resting state. Expression was observed only upon disruption of the epithelial barrier, with a six- to sevenfold increase (P = 0.02) on days 3 and 5 after continuous exposure to DSS. During the development of colitis, clinical disease scores were reduced by 50% (P < 0.001), and histological indices of colitis were one-third less in hIL-37tg mice compared with WT counterparts (P < 0.001). Reduced inflammation was associated with decreased leukocyte recruitment into the colonic lamina propria. In addition, release of IL-1β and TNFα from ex vivo colonic explant tissue was decreased 5- and 13-fold, respectively, compared with WT (P ≤ 0.005), whereas IL-10 was increased sixfold (P < 0.001). However, IL-10 was not required for the anti-inflammatory effects of IL-37 because IL-10-receptor antibody blockade did not reverse IL-37-mediated protection. Mechanistically, IL-37 originating from hematopoietic cells was sufficient to exert anti-inflammatory effects because WT mice reconstituted with hIL-37tg bone marrow were protected from colitis. Thus, IL-37 emerges as key modulator of intestinal inflammation.