Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria.

Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1ß production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1ß release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33-NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM.

Gut eosinophils and their impact on the mucus-resident microbiota.

The gut has the largest commensal bacterial population in the body and its composition can be impacted by host factors such as production of immunoglobulin A (IgA). Eosinophils in the gut have been implicated in the production of antibacterial factors and maintenance of IgA-secreting plasma cells. We used an eosinophil-deficient mouse (∆dblGATA-1-/- ) and littermate controls to investigate the role of eosinophils in the regulation of the microbiota, with particular emphasis on mucus-resident species in the small and large intestine. We found no differences in IgA production or IgA-expressing plasma cells between naive littermates in the small or large intestine. However, denaturing gel gradient electrophoresis revealed differences in the bacterial communities of the mucus and stools between wild-type mice and ∆dblGATA-1-/- mice, with the greatest separation between the mucus microbial communities. Mucus-resident bacteria in ∆dblGATA-1-/- mice had reduced diversity in the mucus compared with the stools. A quantitative PCR panel of selected bacteria showed that the most significant differences in the microbiota were between mucus-resident bacteria and those in stool, such as the abundance of Clostridiales and Bacteroides. Our data implicate eosinophils in the regulation of the microbiota, especially the bacteria most hyperlocal to the gut barrier. Although we see differences between host genotypes in the overall microbial communities, further work is required to establish specifically which bacteria are different between these groups. Most importantly, the data revealed that the mucus and stool microbiota are discrete communities. Stool analysis alone may be insufficient to comprehensively explore and define the role of the gut microbiota in health and disease.

A quantitative brain map of experimental cerebral malaria pathology.

The murine model of experimental cerebral malaria (ECM) has been utilised extensively in recent years to study the pathogenesis of human cerebral malaria (HCM). However, it has been proposed that the aetiologies of ECM and HCM are distinct, and, consequently, no useful mechanistic insights into the pathogenesis of HCM can be obtained from studying the ECM model. Therefore, in order to determine the similarities and differences in the pathology of ECM and HCM, we have performed the first spatial and quantitative histopathological assessment of the ECM syndrome. We demonstrate that the accumulation of parasitised red blood cells (pRBCs) in brain capillaries is a specific feature of ECM that is not observed during mild murine malaria infections. Critically, we show that individual pRBCs appear to occlude murine brain capillaries during ECM. As pRBC-mediated congestion of brain microvessels is a hallmark of HCM, this suggests that the impact of parasite accumulation on cerebral blood flow may ultimately be similar in mice and humans during ECM and HCM, respectively. Additionally, we demonstrate that cerebrovascular CD8+ T-cells appear to co-localise with accumulated pRBCs, an event that corresponds with development of widespread vascular leakage. As in HCM, we show that vascular leakage is not dependent on extensive vascular destruction. Instead, we show that vascular leakage is associated with alterations in transcellular and paracellular transport mechanisms. Finally, as in HCM, we observed axonal injury and demyelination in ECM adjacent to diverse vasculopathies. Collectively, our data therefore shows that, despite very different presentation, and apparently distinct mechanisms, of parasite accumulation, there appear to be a number of comparable features of cerebral pathology in mice and in humans during ECM and HCM, respectively. Thus, when used appropriately, the ECM model may be useful for studying specific pathological features of HCM.

X-ray micro-computed tomography (µCT): an emerging opportunity in parasite imaging.

X-ray micro-computed tomography (µCT) is a technique which can obtain three-dimensional images of a sample, including its internal structure, without the need for destructive sectioning. Here, we review the capability of the technique and examine its potential to provide novel insights into the lifestyles of parasites embedded within host tissue. The current capabilities and limitations of the technology in producing contrast in soft tissues are discussed, as well as the potential solutions for parasitologists looking to apply this technique. We present example images of the mouse whipworm Trichuris muris and discuss the application of µCT to provide unique insights into parasite behaviour and pathology, which are inaccessible to other imaging modalities.

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3.

Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated speck-like protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.

P2X7 receptor-dependent tuning of gut epithelial responses to infection.

Infection and injury of the gut are associated with cell damage and release of molecules such as extracellular adenosine 5'-triphosphate (ATP), which is recognised by the purinergic P2X7 receptor (P2X7R). P2X7R is widely expressed in the gut by antigen-presenting cells (APCs) and epithelial cells, but the role of the P2X7R on epithelial cells is poorly understood. We investigated P2X7R in intestinal epithelium in vitro and in vivo using two model infections, Toxoplasma gondii and Trichinella spiralis. Lipopolysaccharide and ATP treatment of intestinal epithelial cells and infection with T. gondii in vitro did not promote inflammasome-associated interleukin-1ß (IL-1ß) or IL-18 secretion, but promoted C-C motif chemokine ligand 5 (CCL5), tumour necrosis factor-α and IL-6 production that were significantly reduced when the P2X7R was blocked. Similarly, in vivo, infection with either T. spiralis or T. gondii induced rapid upregulation of epithelial CCL5 in wild-type (wild-type (WT)) mice that was significantly reduced in P2X7R-/- littermate controls. The effects of reduced epithelial CCL5 were assayed by investigating recruitment of dendritic cells (DCs) to the epithelium. Infection induced a rapid recruitment of CD11c+CD103+ DC subsets into the epithelial layer of WT mice but not P2X7R-/- mice. In vitro chemotaxis assays and bone marrow chimeras demonstrated the importance of epithelial P2X7R in DC recruitment. P2X7R signalling in epithelial cells mediates chemokine responses to promote initiation of host immunity to infection.

Eosinophils may play regionally disparate roles in influencing IgA(+) plasma cell numbers during large and small intestinal inflammation.

BACKGROUND: Eosinophils are innate immune cells present in the intestine during steady state conditions. An intestinal eosinophilia is a hallmark of many infections and an accumulation of eosinophils is also observed in the intestine during inflammatory disorders. Classically the function of eosinophils has been associated with tissue destruction, due to the release of cytotoxic granule contents. However, recent evidence has demonstrated that the eosinophil plays a more diverse role in the immune system than previously acknowledged, including shaping adaptive immune responses and providing plasma cell survival factors during the steady state. Importantly, it is known that there are regional differences in the underlying immunology of the small and large intestine, but whether there are differences in context of the intestinal eosinophil in the steady state or inflammation is not known. RESULTS: Our data demonstrates that there are fewer IgA(+) plasma cells in the small intestine of eosinophil-deficient ΔdblGATA-1 mice compared to eosinophil-sufficient wild-type mice, with the difference becoming significant post-infection with Toxoplasma gondii. Remarkably, and in complete contrast, the absence of eosinophils in the inflamed large intestine does not impact on IgA(+) cell numbers during steady state, and is associated with a significant increase in IgA(+) cells post-infection with Trichuris muris compared to wild-type mice. Thus, the intestinal eosinophil appears to be less important in sustaining the IgA(+) cell pool in the large intestine compared to the small intestine, and in fact, our data suggests eosinophils play an inhibitory role. The dichotomy in the influence of the eosinophil over small and large intestinal IgA(+) cells did not depend on differences in plasma cell growth factors, recruitment potential or proliferation within the different regions of the gastrointestinal tract (GIT). CONCLUSIONS: We demonstrate for the first time that there are regional differences in the requirement of eosinophils for maintaining IgA+ cells between the large and small intestine, which are more pronounced during inflammation. This is an important step towards further delineation of the enigmatic functions of gut-resident eosinophils.

Lactobacillus rhamnosus GG inhibits the toxic effects of Staphylococcus aureus on epidermal keratinocytes.

Few studies have evaluated the potential benefits of the topical application of probiotic bacteria or material derived from them. We have investigated whether a probiotic bacterium, Lactobacillus rhamnosus GG, can inhibit Staphylococcus aureus infection of human primary keratinocytes in culture. When primary human keratinocytes were exposed to S. aureus, only 25% of the keratinocytes remained viable following 24 h of incubation. However, in the presence of 10(8) CFU/ml of live L. rhamnosus GG, the viability of the infected keratinocytes increased to 57% (P = 0.01). L. rhamnosus GG lysates and spent culture fluid also provided significant protection to keratinocytes, with 65% (P = 0.006) and 57% (P = 0.01) of cells, respectively, being viable following 24 h of incubation. Keratinocyte survival was significantly enhanced regardless of whether the probiotic was applied in the viable form or as cell lysates 2 h before or simultaneously with (P = 0.005) or 12 h after (P = 0.01) S. aureus infection. However, spent culture fluid was protective only if added before or simultaneously with S. aureus. With respect to mechanism, both L. rhamnosus GG lysate and spent culture fluid apparently inhibited adherence of S. aureus to keratinocytes by competitive exclusion, but only viable bacteria or the lysate could displace S. aureus (P = 0.04 and 0.01, respectively). Furthermore, growth of S. aureus was inhibited by either live bacteria or lysate but not spent culture fluid. Together, these data suggest at least two separate activities involved in the protective effects of L. rhamnosus GG against S. aureus, growth inhibition and reduction of bacterial adhesion.

Nod2 deficiency impairs inflammatory and epithelial aspects of the cutaneous wound-healing response.

Infection is a significant causative factor in human chronic wounds that fail to heal. Complex innate host response mechanisms have evolved whereby potentially harmful pathogens are recognized by multiple host pattern recognition receptors (PRRs), yet understanding of PRR function, or dysfunction, in the context of chronic wounds remains limited. NOD2, a cytoplasmic PRR, has been strongly implicated in chronic inflammation of the gut, where loss-of-function mutations have been linked to Crohn's disease; however, cutaneous Nod2 function remains poorly characterized. Here we demonstrate an important role for Nod2 in murine skin wound healing. Cutaneous Nod2 is induced in key wound cell types in response to injury. In the absence of Nod2, mice display a substantial delay in acute wound repair associated with epithelial and inflammatory changes. Specifically, Nod2-null mice display altered epidermal migration and proliferation, an initial delay in neutrophil recruitment associated with decreased expression of the chemokine receptor CXCR2, and reduced numbers of alternatively activated macrophages (Ym1(+) cells). Somewhat surprisingly, these Nod2-null phenotypes were associated with little or no expression change in other PRRs, even though compensatory mechanisms have been shown to exist. In this study we show that healing in TLR2-null mice was essentially normal. These findings reveal a novel intrinsic role for Nod2 in cutaneous wound repair in addition to its role in recognizing invading pathogens.

A culture shift to support public involvement and engagement in research.

The need to empower people to understand their health and well-being has never been greater. However, current research culture does not necessarily prioritize public involvement and engagement, and many scientists are left under-equipped to reap its benefits. Here, we outline both the positive need for purposeful public involvement and engagement in biomedical research and major systemic challenges. While some of our examples stem from the UK, we believe the learnings from them have global significance.

An Epidermal-Specific Role for Arginase1 during Cutaneous Wound Repair.

Nonhealing wounds are a major area of unmet clinical need remaining problematic to treat. Improved understanding of prohealing mechanisms is invaluable. The enzyme arginase1 (ARG1) is involved in prohealing responses, with its role in macrophages best characterized. ARG1 is also expressed by keratinocytes; however, ARG1 function in these critical wound repair cells is not understood. We characterized ARG1 expression in keratinocytes during normal cutaneous repair and reveal de novo temporal and spatial expression at the epidermal wound edge. Interestingly, epidermal ARG1 expression was decreased in both human and murine delayed healing wounds. We therefore generated a keratinocyte-specific ARG1-null mouse model (K14-cre;Arg1fl/fl) to explore arginase function. Wound repair, linked to changes in keratinocyte proliferation, migration, and differentiation, was significantly delayed in K14-cre;Arg1fl/fl mice. Similarly, using the arginase inhibitor N(omega)-hydroxy-nor-L-arginine, human in vitro and ex vivo models further confirmed this finding, revealing the importance of the downstream polyamine pathway in repair. Indeed, restoring the balance in ARG1 activity through the addition of putrescine proved beneficial in wound closure. In summary, we show that epidermal ARG1 plays, to our knowledge, a previously unreported intrinsic role in cutaneous healing, highlighting epidermal ARG1 and the downstream mediators as potential targets for the therapeutic modulation of wound repair.

Impact of a Novel, Low-Cost and Sustainable Health Education Program on the Knowledge, Attitudes, and Practices Related to Intestinal Schistosomiasis in School Children in a Hard-to-Reach District of Madagascar.

Schistosomiasis control requires multisectoral approaches including praziquantel treatment, access to safe water, sanitation and hygiene, and health education. Community input can help ensure health education programs are culturally appropriate to effectively direct protective behavior change. This study reports on the three-stage development of an education program for Malagasy children, with an impact evaluation on their knowledge, attitudes, and practices (KAP) related to intestinal schistosomiasis. A cross-sectional study took place in 2017 with follow-up in 2018 in the hard-to-reach Marolambo district, Madagascar. A novel schistosomiasis education program (SEP) was designed in collaboration with researchers, stakeholders, and local community and included cartoon books, games, songs, puzzles, and blackboard lessons, costing $10 USD per school. KAP questionnaires were completed by 286 children pre-SEP and 273 children post-SEP in 2017, and by 385 and 337 children pre-SEP and post-SEP, respectively, in 2018. Improvements were observed in responses to all questions between pre- and post-education answers in 2017 (53-77%, P < 0.0001) and 2018 (72-98%, P < 0.0001) and in the pre-education answers between years (53-72%, P < 0.0001). Praziquantel mass drug administration attendance improved, rising from 64% to 91% (P < 0.0001), alongside improved latrine use, from 89% to 96% (P = 0.005). This community-consulted and -engaged SEP resulted in substantial improvements in children's understanding of schistosomiasis, with improvements in praziquantel uptake and latrine use. Socioculturally tailored education programs can help gain schistosomiasis control. Continued investment in SEP will help promote the future well-being of children through increased participation in control and treatment activities.

Rapid dendritic cell mobilization to the large intestinal epithelium is associated with resistance to Trichuris muris infection.

The large intestine is a major site of infection and disease, yet little is known about how immunity is initiated within this site and the role of dendritic cells (DCs) in this process. We used the well-established model of Trichuris muris infection to investigate the innate response of colonic DCs in mice that are inherently resistant or susceptible to infection. One day postinfection, there was a significant increase in the number of immature colonic DCs in resistant but not susceptible mice. This increase was sustained at day 7 postinfection in resistant mice when the majority of the DCs were mature. There was no increase in DC numbers in susceptible mice until day 13 postinfection. In resistant mice, most colonic DCs were located in or adjacent to the epithelium postinfection. There were also marked differences in the expression of colonic epithelial chemokines in resistant mice and susceptible mice. Resistant mice had significantly increased levels of epithelium-derived CCL2, CCL3, CCL5, and CCL20 compared with susceptible mice. Furthermore, administering neutralizing CCL5 and CCL20 Abs to resistant mice prevented DC recruitment. This study provides clear evidence of differences in the kinetics of DC responses in hosts inherently resistant and susceptible to infection. DC responses in the colon correlate with resistance to infection. Differences in the production of DC chemotactic chemokines by colonic epithelial cells in response to infection in resistant vs susceptible mice may explain the different kinetics of the DC response.

Maintenance of Barrier Tissue Integrity by Unconventional Lymphocytes.

Mucosal surfaces, as a first barrier with the environment are especially susceptible to damage from both pathogens and physical trauma. Thus, these sites require tightly regulated repair programs to maintain barrier function in the face of such insults. Barrier sites are also enriched for unconventional lymphocytes, which lack rearranged antigen receptors or express only a limited range of such receptors, such as ILCs (Innate Lymphoid Cells), γδ T Cells and MAIT (Mucosal-Associated Invariant T Cells). Recent studies have uncovered critical roles for unconventional lymphocytes in regulating mucosal barrier function, and, in particular, have highlighted their important involvement in barrier repair. The production of growth factors such as amphiregulin by ILC2, and fibroblast growth factors by γδ T cells have been shown to promote tissue repair at multiple barrier sites. Additionally, MAIT cells have been shown to exhibit pro-repair phenotypes and demonstrate microbiota-dependent promotion of murine skin healing. In this review we will discuss how immune responses at mucosal sites are controlled by unconventional lymphocytes and the ways in which these cells promote tissue repair to maintain barrier integrity in the skin, gut and lungs.

Cage and maternal effects on the bacterial communities of the murine gut.

Findings from gut microbiome studies are strongly influenced by both experimental and analytical factors that can unintentionally bias their interpretation. Environment is also critical. Both co-housing and maternal effects are expected to affect microbiomes and have the potential to confound other manipulated factors, such as genetics. We therefore analysed microbiome data from a mouse experiment using littermate controls and tested differences among genotypes (wildtype versus colitis prone-mdr1a-/-), gut niches (stool versus mucus), host ages (6 versus 18 weeks), social groups (co-housed siblings of different genotypes) and maternal influence. We constructed a 16S phylogenetic tree from bacterial communities, fitting random forest models using all 428,234 clades identified. Models discriminated all criteria except host genotype, where no community differences were found. Host social groups differed in abundant, low-level, taxa whereas intermediate phylogenetic and abundance scales distinguished ages and niches. Thus, a carefully controlled experiment treating evolutionary clades of microbes equivalently without reference to taxonomy, clearly identifies whether and how gut microbial communities are distinct across ecologically important factors (niche and host age) and other experimental factors, notably cage effects and maternal influence. These findings highlight the importance of considering such environmental factors in future microbiome studies.

Arginase Signalling as a Key Player in Chronic Wound Pathophysiology and Healing.

Arginase (ARG) represents an important evolutionarily conserved enzyme that is expressed by multiple cell types in the skin. Arg acts as the mediator of the last step of the urea cycle, thus providing protection against excessive ammonia under homeostatic conditions through the production of L-ornithine and urea. L-ornithine represents the intersection point between the ARG-dependent pathways and the urea cycle, therefore contributing to cell detoxification, proliferation and collagen production. The ARG pathways help balance pro- and anti-inflammatory responses in the context of wound healing. However, local and systemic dysfunctionalities of the ARG pathways have been shown to contribute to the hindrance of the healing process and the occurrence of chronic wounds. This review discusses the functions of ARG in macrophages and fibroblasts while detailing the deleterious implications of a malfunctioning ARG enzyme in chronic skin conditions such as leg ulcers. The review also highlights how ARG links with the microbiota and how this impacts on infected chronic wounds. Lastly, the review depicts chronic wound treatments targeting the ARG pathway, alongside future diagnosis and treatment perspectives.

Morphological variability in the mucosal attachment site of Trichuris muris revealed by X-ray microcomputed tomography.

Parasitic infections can be challenging to study because two dimensional light and electron microscopy are often limited in visualising complex and inaccessible attachment sites. Exemplifying this, Trichuris spp. inhabit a tunnel of epithelial cells within the host caecum and colon. A significant global burden of this infection persists, partly because available anthelminthics lack efficacy, although the mechanisms underlying this remain unknown. Consequently, there is a need to pioneer new approaches to better characterize the parasite niche within the host and investigate how variation in its morphology and integrity may contribute to resistance to therapeutic intervention. To address these aims, we exploited three-dimensional X-ray micro-computed tomography (microCT) to image the mouse whipworm, Trichuris muris, in caeca of wild-type C57BL/6 and SCID mice ex vivo. Using osmium tetroxide staining to effectively enhance the contrast of worms, we found that a subset exhibited preferential positioning towards the bases of the intestinal crypts. Moreover, in one rare event, we demonstrated whipworm traversal of the lamina propria. This morphological variability contradicts widely accepted conclusions from conventional microscopy of the parasite niche, showing Trichuris in close contact with the host proliferative and immune compartments that may facilitate immunomodulation. Furthermore, by using a skeletonization-based approach we demonstrate considerable variation in tunnel length and integrity. The qualitative and quantitative observations provide a new morphological point of reference for future in vitro study of host-Trichuris interactions, and highlight the potential of microCT to characterise enigmatic host-parasite interactions more accurately.

Five-Year Follow-Up on the Prevalence and Intensity of Infections of Schistosoma mansoni in a Hard-to-Reach District of Madagascar.

Schistosomiasis is a major public health problem in Madagascar. The WHO recommends preventive chemotherapy by mass drug administration (MDA) with praziquantel as the primary approach to control Schistosoma mansoni-related morbidity in endemic populations, alongside complementary interventions such as health education. The impact of annual MDA and health education programs was assessed in the hard-to-reach Marolambo district of eastern Madagascar, an area endemic for S. mansoni. Repeated cross-sectional studies undertaken 2015-2019 examined between 300 and 381 school-aged children (aged 5-14 years) annually. The prevalence and infection intensity of S. mansoni were assessed by urine-circulating cathodic antigen (CCA) dipsticks and coproscopy using Kato-Katz (KK) methodologies. After four rounds of annual MDA, a reduction in S. mansoni prevalence was seen in CCA (93.9% in year 1-87.7% in year 5; P = 0.007) and KK (73.9% in year 1-59.4% in year 5; P < 0.0001). The prevalence of heavy-intensity infections roughly halved from 23.7% to 10.1% (P < 0.0001), and the mean intensity of infection fell by 55.0% (480.2-216.3 eggs per gram of feces). A malacological survey found Biomphalaria pfeifferi snail intermediate hosts in multiple water contact sites including rice paddies, streams, and Nosivolo River. Despite reductions in infection prevalence and intensity, schistosomiasis still poses a significant public health challenge in Marolambo district. Twice yearly MDA cycles and/or community-wide MDA are suggested to better reduce infections. Expanding health education, improving standards of water, sanitation and hygiene, and attention on snail-related control will also be important, especially in rice paddy irrigated areas.

Characterisation of cuticular inflation development and ultrastructure in Trichuris muris using correlative X-ray computed tomography and electron microscopy.

The parasitic nematode Trichuris trichiura is a significant burden on public health in developing countries, and currently available drugs exhibit a poor cure rate. Worms live within a specialised tunnel of host intestinal epithelial cells and have anterior-ventral projections of the cuticle termed "cuticular inflations", which are thought to be involved in host-parasite interactions. This work aimed to characterise structure and suggest a function of cuticular inflations in the most tractable and widely-used model of trichuriasis, Trichuris muris. Using scanning electron microscopy, we show for the first time that most cuticular inflations develop between the second and third larval moults. Correlative X-ray computed tomography (CT)-steered Serial Block Face Scanning Electron Microscopy (SBF-SEM) and transmission electron microscopy enabled ultrastructural imaging of cuticular inflations, and showed the presence of an additional, web-like layer of cuticle between the median and cortical layers of the inflation. Additionally, we characterised variation in inflation morphology, resolving debate as to the inflations' true shape in situ. Cells underlying the inflations had many mitochondria, and we highlight their potential capacity for active transport as an area for future investigation. Overall, insights from the powerful imaging techniques used provide an excellent basis for future study of cuticular inflation function.

Differential Expression of Soluble Receptor for Advanced Glycation End-products in Mice Susceptible or Resistant to Chronic Colitis.

BACKGROUND: Identifying the factors that contribute to chronicity in inflamed colitic tissue is not trivial. However, in mouse models of colitis, we can investigate at preclinical timepoints. We sought to validate murine Trichuris muris infection as a model for identification of factors that promote development of chronic colitis. METHODS: We compared preclinical changes in mice with a resolving immune response to T. muris (resistant) vs mice that fail to expel the worms and develop chronic colitis (susceptible). Findings were then validated in healthy controls and patients with suspected or confirmed IBD. RESULTS: The receptor for advanced glycation end products (RAGE) was highly dysregulated between resistant and susceptible mice before the onset of any pathological signs. Increased soluble RAGE (sRAGE) in the serum and feces of resistant mice correlated with reduced colitis scores. Mouse model findings were validated in a preliminary clinical study: fecal sRAGE was differentially expressed in patients with active IBD compared with IBD in remission, patients with IBD excluded, or healthy controls. CONCLUSIONS: Preclinical changes in mouse models can identify early pathways in the development of chronic inflammation that human studies cannot. We identified the decoy receptor sRAGE as a potential mechanism for protection against chronic inflammation in colitis in mice and humans. We propose that the RAGE pathway is clinically relevant in the onset of chronic colitis and that further study of sRAGE in IBD may provide a novel diagnostic and therapeutic target.