Recently Updated Role of Chitinase 3-like 1 on Various Cell Types as a Major Influencer of Chronic Inflammation.

Chitinase 3-like 1 (also known as CHI3L1 or YKL-40) is a mammalian chitinase that has no enzymatic activity, but has the ability to bind to chitin, the polymer of N-acetylglucosamine (GlcNAc). Chitin is a component of fungi, crustaceans, arthropods including insects and mites, and parasites, but it is completely absent from mammals, including humans and mice. In general, chitin-containing organisms produce mammalian chitinases, such as CHI3L1, to protect the body from exogenous pathogens as well as hostile environments, and it was thought that it had a similar effect in mammals. However, recent studies have revealed that CHI3L1 plays a pathophysiological role by inducing anti-apoptotic activity in epithelial cells and macrophages. Under chronic inflammatory conditions such as inflammatory bowel disease and chronic obstructive pulmonary disease, many groups already confirmed that the expression of CHI3L1 is significantly induced on the apical side of epithelial cells, and activates many downstream pathways involved in inflammation and carcinogenesis. In this review article, we summarize the expression of CHI3L1 under chronic inflammatory conditions in various disorders and discuss the potential roles of CHI3L1 in those disorders on various cell types.

Brown-Kurume Exchange Programs Have Developed Through Many Unexpected Encounters and Relationships.

In July 1992, my 24 years of studying abroad in the US as a researcher at Harvard Medical School started. During this period, I met many outstanding scholars who conducted some of the world's leading research projects. In particular, the opportunity to collaborate with Dr. Jack A. Elias, Professor and Dean Emeritus of the Faculty of Medicine at Brown University, on a project focusing on a molecule called Chitinase 3-like 1 was very helpful to my career, and eventually led to my current position as Professor in charge of international medical exchange at Kurume University School of Medicine. By strengthening the foundation of our exchange programs and actively promoting international joint research projects, I would like to raise the global name recognition of Kurume University.

Does caffeine have a double-edged sword role in inflammation and carcinogenesis in the colon?

Caffeine (1,3,7-trimethylxanthine, also abbreviated to CAF) is a natural chemical with stimulant effects and is commonly included in many drinks and foods, including coffee, tea, cola, energy drinks, cocoa, chocolates, and so on. Our group previously reported that oral administration of CAF efficiently suppressed the development of intestinal inflammation in a dextran sulfate sodium (DSS)-induced murine acute colitis model by suppressing the expression of chitinase 3-like 1, one of the mammalian chitinases without enzymatic activity. Chitinases are hydrolytic enzymes that break down chitin, a polymer of N-acetylglucosamine, and chitinase-like proteins have no enzymatic activity with preserving chitin-binding ability. CAF binds a cleft of the chitinase active site and plays a role as a pan-chitinase inhibitor. Although CAF showed an anti-inflammatory effect in the above model, oral administration of low-dose CAF with 10% sucrose showed potentially neoplastic effects in colonic epithelial cells in a DSS-induced murine chronic colitis model. In this review, we would like to discuss the pros and cons of coffee/CAF in colonic inflammation and neoplasia with an example of pathological finding.

Chitinase 3-like 1, Carcinoembryonic Antigen-related Cell Adhesion Molecule 6, and Ectopic Claudin-2 in the Carcinogenic Processes of Ulcerative Colitis.

BACKGROUND/AIM: The cumulative cancerous rate of colitis-associated cancer (CAC) has increased exponentially in patients with ulcerative colitis (UC). We have investigated the factors involved in the carcinogenic processes of CAC among UC patients. PATIENTS AND METHODS: A total of 42 UC patients who underwent surgical treatments between January 2001 and December 2010 at Kurume University Hospital (Fukuoka, Japan) were enrolled. We conducted this study using 3 cases of CAC out of 42 UC cases and 1 case of colorectal cancer. cDNA microarray analyses were performed using normal, inflamed, and cancerous tissues from surgical CAC specimens and protein expression was confirmed by immunohistochemical analyses. RESULTS: cDNA microarray revealed 32 genes that were dominantly expressed in tumorous regions of CAC. Gene ontology analysis revealed that these genes were involved in inflammatory responses and cytokine-cytokine receptor interactions. Chitinase 3-like1 (CHI3L1), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), and Claudin-2 (CLND2) were selected from CAC-related genes as candidate molecules. Immunostaining revealed strong expression of each protein in cancerous regions. CONCLUSION: In this study, we identified CAC-related genes and found that CHI3L1, CEACAM6, and CLND2 were expressed in patient samples. All the above genes were associated with adherent invasive Escherichia coli (AIEC), which suggested that these molecules are likely involved in AIEC infection. Further analyses would be required to reveal unknown mechanisms of CAC-related genes in the tumor microenvironment.

Landscape of inflammatory bowel disease in Singapore.

Inflammatory bowel disease (IBD), primarily Crohn's disease and ulcerative colitis, had been widely recognized to affect the Western population. However, the notable rise in prevalence of IBD in Asia, including Singapore, had garnered much attention to the causal role of the shift in trend, and more importantly, effective and safe management of the conditions of these groups of patients in terms of therapy, healthcare economics as well as patient well-being. This review presents a summary of the current landscape of IBD in Singapore, and discuss on areas that can be explored to improve and better understand the local condition, as prevalence continues to grow.

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19.

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.

A Review of Selected IBD Biomarkers: From Animal Models to Bedside.

Inflammatory bowel disease (IBD) is a dysregulated inflammatory condition induced by multiple factors. The etiology of IBD is largely unknown, and the disease progression and prognosis are variable and unpredictable with uncontrolled disease behavior. Monitoring the status of chronic colitis closely is challenging for physicians, because the assessment of disease activity and severity require invasive methods. Using laboratory biomarkers may provide a useful alternative to invasive methods in the diagnosis and management of IBD. Furthermore, patients with ulcerative colitis or Crohn's disease are also at risk of developing cancer. Annual colonoscopies can help lower the risk for developing colorectal cancer. However, laboratory biomarkers may also be helpful as non-invasive indicators in predicting treatment responses, improving prognosis, and predicting possible tumors. This review addresses selected laboratory biomarkers (including ANCA, chitinase 3-like 1, S100A12/RAGE, calprotectin, and TNF/TNFR2), which are identified by utilizing two well-accepted animal models of colitis, dextran sodium sulfate-induced and T cell receptor alpha knockout colitis models. In addition to being useful for monitoring disease severity, these biomarkers are associated with therapeutic strategies. The factors may regulate the initiation and perpetuation of inflammatory factors in the gut.

Chitinase 3-like-1 is a Therapeutic Target That Mediates the Effects of Aging in COVID-19.

COVID-19 is caused by the SARS-CoV-2 (SC2) virus and is more prevalent and severe in the elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor ACE2 and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging and that anti-CHI3L1, kasugamycin and inhibitors of phosphorylation, abrogate these ACE2- and SPP- inductive events. Human studies also demonstrated that the levels of circulating CHI3L1 are increased in the elderly and patients with CM where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP; that this induction is a major mechanism contributing to the effects of aging during SC2 infection and that CHI3L1 coopts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.

Recent updates on the basic mechanisms and pathogenesis of inflammatory bowel diseases in experimental animal models.

The specific pathogenesis underlining inflammatory bowel disease (IBD) is very complicated, and it is further more difficult to clearly explain the pathophysiology of 2 major forms of IBD, Crohn's disease (CD) and ulcerative colitis (UC), and both disorders affect individuals throughout life. Despite every extensive effort, the interplay among genetic factors, immunological factors, environmental factors and intestinal microbes is still completely unrevealed. Animal models are indispensable to find out mechanistic details that will facilitate better preclinical setting to target specific components involved in the pathogenesis of IBD. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, not only IBD but also colon cancer, obesity, psoriasis as well as allergic disorders, in both human and animal models. Advanced technologies including cell-specific and inducible knockout systems, which are recently employed to mouse IBD models, have further enhanced the ability of developing new therapeutic strategies for IBD. Furthermore, data from these mouse models highlight the critical involvement of dysregulated immune responses and impaired colonic epithelial defense system in the pathogenesis of IBD. In this review, we will explain from the history of animal models of IBD to the recent reports of the latest compounds, therapeutic strategies, and approaches tested on IBD animal models.

Clinical importance of IL-22 cascade in IBD.

IL-22 is a relatively new cytokine that is characterized by several unique biological properties. In the intestines, the effect of IL-22 is restricted mainly to non-lymphoid cells such as epithelial cells. Interestingly, the expression pattern and major cellular source of IL-22 have distinct difference between large and small intestines. IL-22 possesses an ability to constitutively activate STAT3 for promoting epithelial cell regeneration and reinforcing mucosal barrier integrity through stimulating the expression of anti-bacterial peptide and mucins. Of note, IL-22 is characterized as a two-faced cytokine that can play not only protective but also deleterious roles in the intestinal inflammation depending on the cytokine environment such as the expression levels of IL-23, T-bet, and IL-22 binding protein. Most importantly, clinical relevance of IL-22 to inflammatory bowel disease has been well highlighted. Mucosal healing, which represents the current therapeutic goal for IBD, can be induced by IL-22. Indeed, indigo naturalis, which can activate IL-22 pathway through Ahr, has been shown in a clinical trial to exhibit a strong therapeutic effect on ulcerative colitis. Despite the beneficial effect of IL-22, continuous activation of the IL-22 pathway increases the risk of colitis-associated cancer, particularly in patients with an extended history of IBD. This review article discusses how IL-22 regulates colitis, how beneficial versus deleterious effects of IL-22 is determined, and why IL-22 represents a promising target for IBD therapy.

CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN.

Tumor necrosis factor (TNF) induces necroptosis, a RIPK3/MLKL-dependent form of inflammatory cell death. In response to infection by Gram-negative bacteria, multiple receptors on macrophages, including TLR4, TNF, and type I IFN receptors, are concurrently activated, but it is unclear how they crosstalk to regulate necroptosis. We report that TLR4 activates CASPASE-8 to cleave and remove the deubiquitinase cylindromatosis (CYLD) in a TRIF- and RIPK1-dependent manner to disable necroptosis in macrophages. Inhibiting CASPASE-8 leads to CYLD-dependent necroptosis caused by the TNF produced in response to TLR4 ligation. While lipopolysaccharides (LPS)-induced necroptosis was abrogated in Tnf(-/-) macrophages, a soluble TNF antagonist was not able to do so in Tnf(+/+) macrophages, indicating that necroptosis occurs in a cell-autonomous manner. Surprisingly, TNF-mediated auto-necroptosis of macrophages requires type I IFN, which primes the expression of key necroptosis-signaling molecules, including TNFR2 and MLKL. Thus, the TNF necroptosis pathway is regulated by both negative and positive crosstalk.

Current Understanding of Dysbiosis in Disease in Human and Animal Models.

Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Although the etiology and pathogenesis of IBD are still largely unknown, dysregulated host/enteric microbial interactions are requisite for the development of IBD. So far, many researchers have tried to identify a precise relationship between IBD and an imbalance of the intestinal microbiota, termed "dysbiosis." Despite extensive efforts, it is still largely unknown about the interplay among microbes, their hosts, and their environments, and whether dysbiosis is a causal factor or an effect of IBD. Recently, deep-sequencing analyses of the microbiota in patients with IBD patients have been instrumental in characterizing the strong association between dysbiosis and IBD development, although it is still unable to identify specific-associated species level changes in most cases. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, including IBD, obesity, and allergic disorders, in both human and animal models. In this review article, the authors have focused on explaining the multiple types of dysbiosis, as well as dysbiosis-related diseases and potential treatments to apply this knowledge to understand a possible cause and potentially find therapeutic strategies for IBD as well as the other dysbiosis-related diseases.

Mechanistic roles of epithelial and immune cell signaling during the development of colitis-associated cancer.

To date, substantial evidence has shown a significant association between inflammatory bowel diseases (IBD) and development of colitis-associated cancer (CAC). The incidence/prevalence of IBD is higher in western countries including the US, Australia, and the UK. Although CAC development is generally characterized by stepwise accumulation of genetic as well as epigenetic changes, precise mechanisms of how chronic inflammation leads to the development of CAC are largely unknown. Preceding intestinal inflammation is one of the major influential factors for CAC tumorigenesis. Mucosal immune responses including activation of aberrant signaling pathways both in innate and adaptive immune cells play a pivotal role in CAC. Tumor progression and metastasis are shaped by a tightly controlled tumor microenvironment which is orchestrated by several immune cells and stromal cells including macrophages, neutrophils, dendritic cells, myeloid derived suppressor cells, T cells, and myofibroblasts. In this article, we will discuss the contributing factors of epithelial as well as immune cell signaling in initiation of CAC tumorigenesis and mucosal immune regulatory factors in the colonic tumor microenvironment. In depth understanding of these factors is necessary to develop novel anti-inflammatory and anti-cancer therapies for CAC in the near future.

Genetically engineered mouse models for studying inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation.

High Endogenous Expression of Chitinase 3-Like 1 and Excessive Epithelial Proliferation with Colonic Tumor Formation in MOLF/EiJ Mice.

Colorectal cancer (CRC) development is mediated by uncontrolled survival and proliferation of tumor progenitor cells. Using animal models to identify and study host-derived factors that underlie this process can aid interventions in preventing tumor expansion and metastasis. In healthy steady states in humans and mice (e.g. C57BL/6 strain), colonic Chitinase 3-like 1 (CHI3L1) gene expression is undetectable. However, this expression can be induced during intestinal inflammation and tumorigenesis where CHI3L1 plays an important role in tissue restitution and cell proliferation. Here, we show that a wild-derived mouse strain MOLF/EiJ expresses high levels of colonic epithelial CHI3L1 at the steady state due to several nucleotide polymorphisms in the proximal promoter regions of the CHI3L1 gene. Interestingly, these mice spontaneously developed polypoid nodules in the colon with signs of immune cell infiltrations at steady state. The CHI3L1 positive colonic epithelial cells were highly proliferative and exhibited malignant transformation and expansion when exposed in vivo to azoxymethane, one of the well-known colonic carcinogens.

Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9.

Many host-factors are inducibly expressed during the development of inflammatory bowel disease (IBD), each having their unique properties, such as immune activation, bacterial clearance, and tissue repair/remodeling. Dysregulation/imbalance of these factors may have pathogenic effects that can contribute to colitis-associated cancer (CAC). Previous reports showed that IBD patients inducibly express colonic chitinase 3-like 1 (CHI3L1) that is further upregulated during CAC development. However, little is known about the direct pathogenic involvement of CHI3L1 in vivo. Here we demonstrate that CHI3L1 (aka Brp39) knockout (KO) mice treated with azoxymethane (AOM)/dextran sulphate sodium (DSS) developed severe colitis but lesser incidence of CAC as compared to that in wild-type (WT) mice. Highest CHI3L1 expression was found during the chronic phase of colitis, rather than the acute phase, and is essential to promote intestinal epithelial cell (IEC) proliferation in vivo. This CHI3L1-mediated cell proliferation/survival involves partial downregulation of the pro-apoptotic S100A9 protein that is highly expressed during the acute phase of colitis, by binding to the S100A9 receptor, RAGE (Receptor for Advanced Glycation End products). This interaction disrupts the S100A9-associated expression positive feedback loop during early immune activation, creating a CHI3L1hi S100A9low colonic environment, especially in the later phase of colitis, which promotes cell proliferation/survival of both normal IECs and tumor cells.

Recent advancement in understanding colitis-associated tumorigenesis.

Chronic inflammation predisposes patients with inflammatory bowel disease to the risk of developing colitis-associated cancer (CAC). Growing evidence strongly suggests that CAC development is multifactorial and is attributed to concurrent, dynamic dysregulations in host immunity, enteric microbiota, and epithelial restitution during the course of chronic inflammation. This article discusses the recent advances in understanding the different forms of CAC that may develop in patients with inflammatory bowel disease and animal models, as well as molecular alterations and other processes that orchestrate the development of CAC.

Regulatory B cells in mouse models of intestinal inflammation.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition with increasing incidence and prevalence around the world. Although B cells had generally been believed to play a pathogenic role in IBD due to the production of autoantibodies, a growing body of evidence from mouse models suggests the coexistence of pathogenic B cells and regulatory B cells, termed Breg, in this disorder. Since some unique techniques are required to closely study the Breg in gut-associated lymphoid tissues (GALT), we herein describe how to induce colitis in mice and how to analyze the phenotype and function of GALT-specific Breg.

Chitinase 3-like 1 synergistically activates IL6-mediated STAT3 phosphorylation in intestinal epithelial cells in murine models of infectious colitis.

BACKGROUND: Chitinase 3-like 1 (CHI3L1) is an inducible molecule on intestinal epithelial cells during the development of inflammatory bowel disease. METHODS: To investigate the role of CHI3L1 in bacterial infectious colitis, we orally inoculated pathogenic Salmonella typhimurium and potentially pathogenic adherent-invasive Escherichia coli (AIEC) LF82 virulent strain into C57Bl/6 wild-type mice or CHI3L1 knockout (KO) mice. RESULTS: Both S. typhimurium and AIEC LF82 were found to efficiently induce severe intestinal inflammation in wild-type mice but not in CHI3L1 KO mice. These bacteria-infected CHI3L1 KO mice exhibit decreased cellular infiltration, bacterial translocation, and production of interleukin (IL)-6 and IL-22, as compared with those of wild-type mice. More importantly, CHI3L1 KO mice displayed aberrant STAT3 activation after bacterial infections. Co-stimulation of CHI3L1 and IL-6, but not IL-22, synergistically activates STAT3 signaling pathway in intestinal epithelial cells in an NF-κB/MAPK-dependent manner. CONCLUSIONS: CHI3L1 promotes the onset of selected gram-negative bacterial infectious colitis through IL-6/STAT3 pathway.

Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease.

Family 18 chitinases have a binding capacity with chitin, a polymer of N-acetylglucosamine. Recent studies strongly suggested that chitinase 3-like 1 (CHI3L1, also known as YKL-40) and acidic mammalian chitinase, the two major members of family 18 chitinases, play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD), bronchial asthma and several other inflammatory disorders. Based on the data from high-throughput screening, it has been found that three methylxanthine derivatives, caffeine, theophylline, and pentoxifylline, have competitive inhibitory effects against a fungal family 18 chitinase by specifically interacting with conserved tryptophans in the active site of this protein. Methylxanthine derivatives are also known as adenosine receptor antagonists, phosphodiesterase inhibitors and histone deacetylase inducers. Anti-inflammatory effects of methylxanthine derivatives have been well-documented in the literature. For example, a beneficial link between coffee or caffeine consumption and type 2 diabetes as well as liver cirrhosis has been reported. Furthermore, theophylline has a long history of being used as a bronchodilator in asthma therapy, and pentoxifylline has an immuno-modulating effect for peripheral vascular disease. However, it is still largely unknown whether these methylxanthine derivative-mediated anti-inflammatory effects are associated with the inhibition of CHI3L1-induced cytoplasmic signaling cascades in epithelial cells. In this review article we will examine the above possibility and summarize the biological significance of methylxanthine derivatives in intestinal epithelial cells. We hope that this study will provide a rationale for the development of methylxanthine derivatives, in particular caffeine, -based anti-inflammatory therapeutics in the field of IBD and IBD-associated carcinogenesis.