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In the version of this article initially published, in the Acknowledgements, the grant number for the Start Grant TWILIGHT awarded to M.A.L. by the European Research Council was omitted. The correct wording is “Supported by...the European Research Council (...Start Grant TWILIGHT (637801) to M.A.L.).” The error has not been corrected in the original article. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Crohn's disease and ulcerative colitis are chronic and progressive inflammatory bowel diseases (IBDs) that are attributed to dysregulated interactions between the gut microbiome and the intestinal mucosaassociated immune system. There are limited studies investigating the role of either IL-1α or IL-1β in mouse models of colitis, and no clinical trials blocking either IL-1 have yet to be performed. In the present study, we show that neutralization of IL-1α by a specific monoclonal antibody against murine IL-1α was highly effective in reducing inflammation and damage in SAMP mice, mice that spontaneously develop a Crohn's-like ileitis. Anti-mouse IL-1α significantly ameliorated the established, chronic ileitis and also protected mice from developing acute DSS-induced colitis. Both were associated with taxonomic divergence of the fecal gut microbiome, which was treatment-specific and not dependent on inflammation. Anti-IL-1α administration led to a decreased ratio of Proteobacteria to Bacteroidetes, decreased presence of Helicobacter species, and elevated representation of Mucispirillum schaedleri and Lactobacillus salivarius. Such modification in flora was functionally linked to the antiinflammatory effects of IL-1α neutralization, as blockade of IL-1α was not effective in germfree SAMP mice. Furthermore, preemptive dexamethasone treatment of DSS-challenged SAMP mice led to changes in flora composition without preventing the development of colitis. Thus, neutralization of IL-1α changes specific bacterial species of the intestinal microbiome, which is linked to its antiinflammatory effects. These functional findings may be of significant value for patients with IBD, who may benefit from targeted IL-1α-based therapies. © 2019 National Academy of Sciences. All rights reserved.

Background TNF-like cytokine 1A (TL1A) and its functional receptor, death-domain-receptor-3 (DR3), are multifunctional mediators of effector and regulatory immunity. We aimed to evaluate the functional role and therapeutic potential of TL1A/DR3 signaling in Crohn's disease-like ileitis. Methods Ileitis-prone SAMP1/YitFc (SAMP) and TNF ΔARE/+ mice were rendered deficient for DR3 or TL1A by microsatellite marker-assisted backcrossing. Pathological and immunological characteristics were compared between control and knockout mice, and mucosal immunophenotype was analyzed by Nanostring microarray assay. The therapeutic effect of pharmacological TL1A neutralization was also investigated. Results DR3 deficiency was associated with restoration of a homeostatic mucosal immunostat in SAMP mice through the regulation of several pro- A nd anti-inflammatory genes. This led to suppression of effector immunity, amelioration of ileitis severity, and compromised ability of either unfractionated CD4 + or CD4 + CD45RB hi mucosal lymphocytes to transfer ileitis to severe combined immunodeficient mice recipients. TNF-driven ileitis was also prevented in TNF ΔARE/+ xDR3 -/- mice, in association with decreased expression of the pro-inflammatory cytokines TNF and IFN-γ. In contrast to DR3, TL1A was dispensable for the development of ileitis although it affected the kinetics of inflammation, as TNF ΔARE/+ xTL1A-/-demonstrated delayed onset of inflammation, whereas administration of a neutralizing, anti-TL1A antibody ameliorated early but not late TNF ΔARE/+ ileitis. Conclusion We found a prominent pro-inflammatory role of DR3 in chronic ileitis, which is only partially mediated via interaction with TL1A, raising the possibility for additional DR3 ligands. Death-domain-receptor-3 appears to be a master regulator of mucosal homeostasis and inflammation and may represent a candidate therapeutic target for chronic inflammatory conditions of the bowel. © 2018 Crohn's and Colitis Foundation. Published by Oxford University Press. All rights reserved.

As one of the leading clothing exporters in the world, Indonesia has the chance to promote the richness of its textile heritage, particularly hand-drawn Batik textile, in the global fashion industry. Batik is an Indonesian fashion heritage, recognized as a UNESCO Intangible Heritage of Humanity since 2009. Apart from its historical production technique, Batik contains outstanding universal values associated with the socio-cultural aspects of Indonesian lives. These include philosophical and spiritual meanings contained in its distinctive motifs, the rules for its wearing, as well as social empowerment. The advances of digital communication can play an important role in communicating and shaping Indonesia’s Batik usage values between tradition and contemporary fashion. This research is presented to identify how Batik is communicated through mobile apps in terms of their contents, functionalities, apps’ purposes, as well as their alignment with UNESCO’s safeguarding narratives.

Patients with inflammatory bowel disease (IBD) are at increased risk for developing colorectal cancer. Evidence suggests that colonic dysplasia and colitis-associated cancer (CAC) are often linked to repeated cycles of epithelial cell injury and repair in the context of chronic production of inflammatory cytokines. Several mouse models of CAC have been proposed, including chemical induction through exposure to dextran sulfate sodium (DSS) with the genotoxic agents azoxymethane (AOM), 1,2-dymethylhydrazine (DHM) or targeted genetic mutations. However, such models are usually performed on healthy animals that usually lack the underlying genetic predisposition, immunological dysfunction and dysbiosis characteristic of IBD. We have previously shown that inbred SAMP1/YitFc (SAMP) mice develop a progressive Crohn's disease (CD)-like ileitis in the absence of spontaneous colitis. We hypothesize that SAMP mice may be more susceptible to colonic tumorigenesis due to their predisposition to IBD. To test this hypothesis, we administered AOM/DSS to IBD-prone SAMP and their non-inflamed parental control strain, AKR mice. Our results showed that AOM/DSS treatment enhanced the susceptibility of colitis in SAMP compared to AKR mice, as assessed by endoscopic and histologic inflammatory scores, daily weight loss and disease activity index (DAI), during and after DSS administration. SAMP mice also showed increased colonic tumorigenesis, resulting in the occurrence of intramucosal carcinoma and a higher incidence of high-grade dysplasia and tumor burden. These phenomena occurred even in the absence of AOM and only upon repeated cycles of DSS. Taken together, our data demonstrate a heightened susceptibility to colonic inflammation and tumorigenesis in AOM/DSS-treated SAMP mice with CD-like ileitis. This novel model represents a useful tool to investigate relevant mechanisms of CAC, as well as for pre-clinical testing of potential IBD and colon cancer therapeutics.

Purpose of review Currently several mouse models are considered representative of inflammatory bowel disease (IBD). This review presents recent developments regarding the role of animal models of intestinal inflammation as research tools in IBD. Recent findings Preclinical studies in animal models of intestinal inflammation have generated novel findings in several areas of IBD research. The combination of chemical and genetically engineered models have revealed protective or harmful roles for various components of the innate immune system in response to acute injury and repair mechanisms for the intestinal mucosa. Advances in the use of endoscopic and radiologic techniques have allowed identification of inflammatory biomarkers and in-vivo monitoring of cell trafficking towards inflammatory sites. Translational research has shed light on pathogenic mechanisms through which recent biological treatments may exert their beneficial effects in patients with IBD. Finally, novel therapies are continuously tested in animal models of IBD as part of preclinical drug development programs. Summary Animal models of intestinal inflammation continue to be important research tools with high significance for understanding the pathogenesis of IBD and exploring novel therapeutic options. Development of additional experimental models that address existing limitations, and more closely resemble the characteristics of Crohn's disease and ulcerative colitis are greatly needed. © 2017 Wolters Kluwer Health, Inc. All rights reserved.

TNF-like cytokine 1A (TL1A) is expressed on APCs and provides costimulatory signals to activated lymphocytes that bear its functional receptor, death receptor 3 (DR3). TL1A/DR3 signaling is involved in the pathogenesis of human and experimental inflammatory bowel disease. In the current study, we investigated the role of this cytokine/receptor pair in acute intestinal injury/repair pathways.We demonstrate that intact DR3 signaling protected mice from acute dextran sodium sulfate colitis because DR3-/- mice showed more severe mucosal inflammation and increased mortality. DR3-/- mice were compromised in their ability to maintain adequate numbers of CD4+CD25+Foxp3+ regulatory T cells in response to acute mucosal damage. This defect in immune regulation led to a nonspecific upregulation of effector proinflammatory pathways, which was most prominent for the Th17 immunophenotype. TL1A-/- mice were similarly more susceptible to dextran sodium sulfate colitis, although without mortality and with delayed kinetics compared with DR3-/- mice, and also displayed significantly reduced numbers of regulatory T cells. Infection of DR3-/- mice with Salmonella typhimurium was associated with defective microbial clearance and elevated bacterial load. Taken together, our findings indicate a novel protective role for the TL1A/DR3 axis in the regulation of mucosal homeostasis during acute intestinal injury/repair, which contrasts with its known pathogenic function during chronic intestinal inflammation. © Copyright 2016 by The American Association of Immunologists, Inc. All rights reserved.

Although a clear association has been established between IL-33 and inflammatory bowel disease, mechanistic studies to date, primarily using acute murine models of colitis, have yielded contradicting results, demonstrating both pathogenic and protective roles. We used a well-characterized, spontaneous model of inflammatory bowel disease [ie, SAMP1/YitFc (SAMP) mice] to investigate the role of IL-33 during chronic intestinal inflammation. Our results showed marked eosinophil infiltration into the gut mucosa with increased levels of eotaxins and type 2 helper T-cell (Th2) cytokines as disease progressed and became more severe, which could be reversed upon either eosinophil depletion or blockade of IL-33 signaling. Exogenous IL-33 administration recapitulated these effects in ilea of uninflamed (parental) control AKR/J mice. Human data supported these findings, showing colocalization and up-regulation of IL-33 and eosinophils in the colonic mucosa of inflammatory bowel disease patients versus noninflamed controls. Finally, colonization of commensal flora by fecal material transplantation into germ-free SAMP and the presence of the gut microbiome induced IL-33, subsequent eosinophil infiltration, and mounting of Th2 immune responses, leading to exacerbation of chronic intestinal inflammation characteristic of SAMP mice. These data demonstrate a pathogenic role for IL-33-mediated eosinophilia and activation of Th2 immunity in chronic intestinal inflammation that is dependent on the gut microbiome. Targeting IL-33 may represent a novel therapeutic approach to treat patients with inflammatory bowel disease. © 2016 American Society for Investigative Pathology.

Purpose of review Cytokines of the intestinal microenvironment largely dictate immunological responses after mucosal insults and the dominance of homeostatic or proinflammatory pathways. This review presents important recent studies on the role of specific cytokines in the pathogenesis of intestinal inflammation. Recent findings The particular mucosal effects of cytokines depend on their inherent properties but also the cellular origin, type of stimulatory antigens, intermolecular interactions, and the particular immunological milieu. Novel cytokines of the interleukin-1 (IL-1) family, including IL-33 and IL-36, have dominant roles in mucosal immunity, whereas more established ones such as IL-18 are constantly enriched with unique properties. Th17 cells are important mucosal constituents, although their profound plasticity, makes the specific set of cytokines they secrete more important than their mere numbers. Finally, various cytokines, such as tumor necrosis factor-a, IL-6, tumor necrosis factor-like cytokine 1A, and death receptor, 3 demonstrate dichotomous roles with mucosa-protective function in acute injury but proinflammatory effects during chronic inflammation. Summary The role of cytokines in mucosal health and disease is increasingly revealed. Such information not only will advance our understanding of the pathogenesis of gut inflammation, but also set the background for development of reliable diagnostic and prognostic biomarkers and cytokine-specific therapies. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that quiescent macrophages acquire a pro-inflammatory activation state and contribute to chronic intestinal inflammation. The transcriptional events governing macrophage activation and gene expression in the context of chronic inflammation such as IBD remain incompletely understood. Here, we identify Kruppel-like transcription factor-6 (KLF6) as a critical regulator of pathogenic myeloid cell activation in human and experimental IBD. We found that KLF6 was significantly upregulated in myeloid cells and intestinal tissue from IBD patients and experimental models of IBD, particularly in actively inflamed regions of the colon. Using complementary gain- and loss-of-function studies, we observed that KLF6 promotes pro-inflammatory gene expression through enhancement of nuclear factor κB (NFκB) signaling, while simultaneously suppressing anti-inflammatory gene expression through repression of signal transducer and activator of transcription 3 (STAT3) signaling. To study the in vivo role of myeloid KLF6, we treated myeloid-specific KLF6-knockout mice (Mac-KLF6-KO) with dextran sulfate sodium (DSS) and found that Mac-KLF6-KO mice were protected against chemically-induced colitis; this highlights the central role of myeloid KLF6 in promoting intestinal inflammation. Collectively, our results point to a novel gene regulatory program underlying pathogenic, pro-inflammatory macrophage activation in the setting of chronic intestinal inflammation.

Purpose of review Type 2 (Th2) immune responses play important roles in intestinal immunity by contributing to the maintenance of mucosal homeostasis, not only conferring protection against helminthic infection but also participating in pro-inflammatory pathways in chronic intestinal inflammatory disorders, including inflammatory bowel disease. The current review focuses on recent developments regarding the role of Th2 responses in intestinal inflammation. Recent findings Th2 gut mucosal responses are promoted by mediators that are released following injury to the epithelium, and act as alarmin-type danger signals. Interleukin (IL)-33 is prominent among such factors and demonstrates a dichotomous function, exerting either protective or pro-inflammatory effects, depending on its cellular compartmentalization. The pool of type 2 effector cells has been enriched recently to include not only classical CD4+ Th2 lymphocytes but also a subset of innate lymphocytes (ILC2s) that express the transcriptional factor GATA binding protein 3 and secrete IL-4, IL-5, and IL-13. ILC2s play important roles during infection with helminths and bi-directionally interact with Th2 CD4+ lymphocytes, thus establishing a transition from innate to adaptive immunological pathways. Th2 responses are also involved in proinflammatory pathways at the intestinal mucosa, and neutralization of the pivotal cytokines IL-4 and IL-13 has been shown to regulate experimental intestinal inflammation. In striking contrast, however, neutralization of human IL-13 had no therapeutic effect in patients with ulcerative colitis. Summary Further studies will be required to delineate the specific mechanisms of type 2 mucosal immunity in inflammatory bowel disease and examine the applicability of Th2-targeted therapies for intestinal inflammation. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Purpose of review: Cytokines are integral mediators for maintaining intestinal mucosal homeostasis, as well as prominent effector molecules during chronic gut inflammatory diseases. This review focuses on recent studies of the role of specific cytokines in mucosal immunity. Recent findings: Dichotomous, or even opposing, functions have been described for several cytokines involved in intestinal innate immunity (most notably for members of the interleukin-1 family), which depend on the specific inflammatory conditions within the intestinal mucosa. For example, both interleukin-1a and interleukin-33 exhibit 'alarmin'-type properties that can signal tissue or cell damage, which further add to their well described proinflammatory roles. Costimulatory molecules of the tumor necrosis factor/tumor necrosis factor receptor superfamily, such as TNF-like cytokine 1A and LIGHT, are actively involved in mucosal proinflammatory pathways, but also may exert protection against infectious agents to facilitate recovery from acute inflammation. Finally, innate lymphoid cells are increasingly recognized as important cellular sources of pivotal mucosal cytokines, including the interleukin-23/T helper 17 cytokine, interleukin-22. Summary: Elucidating the complexity of cytokine signaling within the normal mucosa and during acute and chronic inflammation will be a pivotal step toward understanding the pathogenesis of immune-mediated gut diseases and developing effective therapies to treat them. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Purpose of Review: Tumor necrosis factor (TNF)-like cytokine 1A (TL1A) associates with the death receptor 3 (DR3) on activated lymphocytes and induces proinflammatory signals. The decoy receptor 3 (DcR3) competes for TL1A binding and inhibits functional signaling. This review focuses on the role of the TL1A/DR3/DcR3 cytokine system in inflammatory bowel diseases (IBDs). Recent Findings: TL1A may induce IFN-γ-mediated and IL-17-mediated proinflammatory pathways in IBDs by acting on DR3-expressing, CD4CD161 lymphocytes, which are substantially enriched at the inflamed intestinal mucosa. In addition, TL1A/DR3 signaling results in expansion of the Treg pool with concomitant and transient inhibition of their suppressive function. Constitutive expression of TL1A in transgenic mice was associated with small intestinal inflammation, which was accompanied by colonic fibrosis both spontaneously and under colitogenic conditions. Recent human studies demonstrated that soluble TL1A and DcR3 are present in the systemic circulation in patients with active IBD and decline after successful anti-inflammatory treatment. Summary: TL1A/DR3 interactions may participate in the pathogenesis of chronic intestinal inflammation and offer novel therapeutic targets for patients with ulcerative colitis and Crohn's disease. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background and Aim:Human and animal studies have clearly established tumor necrosis factor (TNF)α as an important mediator of Crohn's disease pathogenesis. However, whether systemic or only local TNFα overproduction is required for the development of chronic intestinal inflammation and Crohn's disease remains unclear. The aim of this study was to assess the contribution of intestinal epithelial-derived TNFα to the development of murine Crohn's-like ileitis. Methods:We adapted the well-established TNFΔARE/+ mouse model of Crohn's disease (which systemically overexpresses TNFα) to generate a homozygous mutant strain that overexpress TNFα only within the intestinal epithelium. Intestinal-specific TNFiΔARE/iΔARE mice were examined for histopathological signs of gut inflammation and extraintestinal manifestations of Crohn's disease. The mucosal immune phenotype was characterized, and the contribution of specific lymphocyte populations to the pathogenesis of TNFiΔARE/iΔARE ileitis was assessed. Results:TNFiΔARE/iΔARE mice had increased mucosal and systemic TNFα levels compared to wild-type controls (P

Administration of exogenous interleukin-1 receptor antagonist (IL-1ra) is effective in reducing the severity of disease in animal models of acute inflammation. However, the function of endogenous IL-1ra in this process, is not yet known. We investigated the pathophysiological role of IL-1ra in a rabbit model of formalin-immune complex colitis. This model has previously been shown to be IL-1 mediated and a reduction in disease severity is observed with exogenous IL-1ra treatment. Colonic IL-1ra was found to be elevated subsequent to IL-1, and exceeded IL-1 levels 10-fold. Peak levels of IL-1ra preceded both the resolution of colitis and a significant decrease in IL-1 production. Administration of specific neutralizing antibodies against rabbit IL-1ra increased mortality and prolonged intestinal inflammatory responses. A significant increase in IL-1 alpha colonic tissue levels was also measured as a result of exogenous anti-IL-1ra treatment. These studies are the first demonstration that endogenous IL-1ra may play an important role in regulating the host's inflammatory response by counteracting the deleterious and possibly lethal effects of IL-1 produced during acute inflammation.