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1.  Chitinase 3-like 1 synergistically activates IL6-mediated STAT3 phosphorylation in intestinal epithelial cells in murine models of infectious colitis 
Inflammatory bowel diseases  2014;20(5):835-846.
Background
Chitinase 3-like 1 (CHI3L1) is an inducible molecule on intestinal epithelial cells (IECs) during the development inflammatory bowel disease (IBD).
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 (WT) or CHI3L1 knockout (KO) mice.
Results
Both S. typhimurium and AIEC LF82 were found to efficiently induce severe intestinal inflammation in WT but not CHI3L1 KO mice. These bacteria-infected CHI3L1 KO mice exhibit decreased cellular infiltration, bacterial translocation and productions of IL-6 and IL-22, as compared to those of WT 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 IECs in an NF-κB/MAPK dependent manner.
Conclusions
CHI3L1 promotes the onset of selected gram-negative bacterial infectious colitis through IL-6/STAT3 pathway.
doi:10.1097/MIB.0000000000000033
PMCID: PMC4012618  PMID: 24694795
chitinase; cytokine; STAT3; intestinal epithelial cells
2.  Chitotriosidase in the Pathogenesis of Inflammation, Interstitial Lung Diseases and COPD 
As a member of 18 glycosyl hydrolase (GH) family, chitotriosidase (Chitinase 1, CHIT1) is a true chitinase mainly expressed in the differentiated and polarized macrophages. CHIT1 is an innate immune mediator that digests the cell walls of chitin-containing eukaryotic pathogens, such as fungi. However, CHIT1 is dysregulated in granulomatous and fibrotic interstitial lung diseases characterized by inflammation and tissue remodeling. These include tuberclosis, sarcoidosis, idiopathic pulmonary fibrosis, scleroderma-associated interstitial lung diseases (SSc-ILD), and chronic obstructive lung diseases (COPD). CHIT1 serum concentration correlates with the progression or the severity of these diseases, suggesting a potential use of CHIT1 as a biomarker or a therapeutic target. Recent studies with genetically modified mice demonstrate that CHIT1 enhances TGF-β1 receptor expression and signaling, suggesting a role in initiating or amplifying the response to organ injury and repair. This additional CHIT1 activity is independent of its enzymatic activity. These studies suggest that CHIT1 serves a bridging function; it is both an innate immune mediator and a regulator of tissue remodeling. This review will focus on recent data linking CHIT1 to the pathogenesis of inflammation, interstitial lung disease, and COPD.
doi:10.4168/aair.2015.7.1.14
PMCID: PMC4274464  PMID: 25553258
Chitotriosidase; sarcoidosis; scleroderma; idiopathic pulmonary fibrosis; inflammation; TGF-beta
3.  Modifiers of TGF-β1 effector function as novel therapeutic targets of pulmonary fibrosis 
Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-β1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-β1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-β1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-β1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-β1 could be an alternative approach that selectively inhibits TGF-β1-stimulated fibrotic tissue response while preserving major physiological function of TGF-β1. Recent studies from our laboratory revealed that TGF-β1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-β1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-β1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-β1 plays a significant role.
doi:10.3904/kjim.2014.29.3.281
PMCID: PMC4028515  PMID: 24851060
Transforming growth factor beta1; Pulmonary fibrosis; Response modifiers; Amphiregulin; Chitotriosidase
4.  Role of Breast Regression Protein–39 in the Pathogenesis of Cigarette Smoke–Induced Inflammation and Emphysema 
The exaggerated expression of chitinase-like protein YKL-40, the human homologue of breast regression protein–39 (BRP-39), was reported in a number of diseases, including chronic obstructive pulmonary disease (COPD). However, the in vivo roles of YKL-40 in normal physiology or in the pathogenesis of specific diseases such as COPD remain poorly understood. We hypothesized that BRP-39/YKL-40 plays an important role in the pathogenesis of cigarette smoke (CS)–induced emphysema. To test this hypothesis, 10-week-old wild-type and BRP-39 null mutant mice (BRP-39−/−) were exposed to room air (RA) and CS for up to 10 months. The expression of BRP-39 was significantly induced in macrophages, airway epithelial cells, and alveolar Type II cells in the lungs of CS-exposed mice compared with RA-exposed mice, at least in part via an IL-18 signaling–dependent pathway. The null mutation of BRP-39 significantly reduced CS-induced bronchoalveolar lavage and tissue inflammation. However, CS-induced epithelial cell apoptosis and alveolar destruction were further enhanced in the absence of BRP-39. Consistent with these findings in mice, the tissue expression of YKL-40 was significantly increased in the lungs of current smokers compared with the lungs of ex-smokers or nonsmokers. In addition, serum concentrations of YKL-40 were significantly higher in smokers with COPD than in nonsmokers or smokers without COPD. These studies demonstrate a novel regulatory role of BRP-39/YKL-40 in CS-induced inflammation and emphysematous destruction. These studies also underscore that maintaining physiologic concentrations of YKL-40 in the lung is therapeutically important in preventing excessive inflammatory responses or emphysematous alveolar destruction.
doi:10.1165/rcmb.2010-0081OC
PMCID: PMC3135840  PMID: 20656949
YKL-40/BRP-39; COPD; emphysema; cigarette smoke
5.  Role of breast regression protein-39/YKL-40 in asthma and allergic responses 
BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40 levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for asthma and other allergic diseases. Here, we present an overview of chitin/chitinase biology and summarize recent findings on the role of BRP-39 in the pathogenesis of asthma and allergic responses.
doi:10.4168/aair.2010.2.1.20
PMCID: PMC2831605  PMID: 20224674
BRP-39; human CHI3L1 protein; asthma; hypersensitivity
6.  Endogenous IL-11 Signaling Is Essential in Th2- and IL-13–Induced Inflammation and Mucus Production 
IL-11 and IL-11 receptor (R)α are induced by Th2 cytokines. However, the role(s) of endogenous IL-11 in antigen-induced Th2 inflammation has not been fully defined. We hypothesized that IL-11, signaling via IL-11Rα, plays an important role in aeroallergen-induced Th2 inflammation and mucus metaplasia. To test this hypothesis, we compared the responses induced by the aeroallergen ovalbumin (OVA) in wild-type (WT) and IL-11Rα–null mutant mice. We also generated and defined the effects of an antagonistic IL-11 mutein on pulmonary Th2 responses. Increased levels of IgE, eosinophilic tissue and bronchoalveolar lavage (BAL) inflammation, IL-13 production, and increased mucus production and secretion were noted in OVA-sensitized and -challenged WT mice. These responses were at least partially IL-11 dependent because each was decreased in mice with null mutations of IL-11Rα. Importantly, the administration of the IL-11 mutein to OVA-sensitized mice before aerosol antigen challenge also caused a significant decrease in OVA-induced inflammation, mucus responses, and IL-13 production. Intraperitoneal administration of the mutein to lung-specific IL-13–overexpressing transgenic mice also reduced BAL inflammation and airway mucus elaboration. These studies demonstrate that endogenous IL-11R signaling plays an important role in antigen-induced sensitization, eosinophilic inflammation, and airway mucus production. They also demonstrate that Th2 and IL-13 responses can be regulated by interventions that manipulate IL-11 signaling in the murine lung.
doi:10.1165/rcmb.2008-0053OC
PMCID: PMC2586049  PMID: 18617680
IL-11; mutein; airway inflammation; mucus; IL-13
7.  P21 Regulates TGF-β1–Induced Pulmonary Responses via a TNF-α–Signaling Pathway 
Transforming growth factor (TGF)-β1 is an essential regulatory cytokine that has been implicated in the pathogenesis of diverse facets of the injury and repair responses in the lung. The types of responses that it elicits can be appreciated in studies from our laboratory that demonstrated that the transgenic (Tg) overexpression of TGF-β1 in the murine lung causes epithelial apoptosis followed by fibrosis, inflammation, and parenchymal destruction. Because a cyclin-dependent kinase inhibitor, p21, is a key regulator of apoptosis, we hypothesized that p21 plays an important role in the pathogenesis of TGF-β1–induced tissue responses. To test this hypothesis we evaluated the effect of TGF-β1 on the expression of p21 in the murine lung. We also characterized the effects of transgenic TGF-β1 in mice with wild-type and null mutant p21 loci. These studies demonstrate that TGF-β1 is a potent stimulator of p21 expression in the epithelial cells and macrophages in the murine lung. They also demonstrate that TGF-β1–induced lung inflammation, fibrosis, myofibroblast accumulation, and alveolar destruction are augmented in the absence of p21, and that these alterations are associated with exaggerated levels of apoptosis and caspase-3 activation. Finally, our studies further demonstrated that TGF-β1 induces p21 via a TNF-α–signaling pathway and that p21 is a negative modulator of TGF-β1–induced TNF-α expression. Collectively, our studies demonstrate that p21 regulates TGF-β1–induced apoptosis, inflammation, fibrosis, and alveolar remodeling by interacting with TNF-α–signaling pathways.
doi:10.1165/rcmb.2007-0276OC
PMCID: PMC2258454  PMID: 17932374
TGF-β; p21; apoptosis; fibrosis; emphysema
8.  Chitin, Chitinases and Chitinase-like Proteins in Allergic Inflammation and Tissue Remodeling 
Yonsei Medical Journal  2009;50(1):22-30.
Chitin, the second most abundant polysaccharide in nature after cellulose, consist exoskeleton of lower organisms such as fungi, crustaceans and insects except mammals. Recently, several studies evaluated immunologic effects of chitin in vivo and in vitro and revealed new aspects of chitin regulation of innate and adaptive immune responses. It has been shown that exogenous chitin activates macrophages and other innate immune cells and also modulates adaptive type 2 allergic inflammation. These studies further demonstrate that chitin stimulate macrophages by interacting with different cell surface receptors such as macrophage mannose receptor, toll-like receptor 2 (TLR-2), C-type lectin receptor Dectin-1, and leukotriene B4 recepptor (BLT1). On the other hand, a number of chitinase or chitinase-like proteins (C/CLP) are ubiquitously expressed in the airways and intestinal tracts from insects to mammals. In general, these chitinase family proteins confer protective functions to the host against exogenous chitin-containing pathogens. However, substantial body of recent studies also set light on new roles of C/CLP in the development and progression of allergic inflammation and tissue remodeling. In this review, recent findings on the role of chitin and C/CLP in allergic inflammation and tissue remodeling will be highlighted and controversial and unsolved issues in this field of studies will be discussed.
doi:10.3349/ymj.2009.50.1.22
PMCID: PMC2649864  PMID: 19259344
Chitin; chitinases; chitinase-like proteins; immunity; remodeling
9.  Role of Chitinase 3–Like-1 in Interleukin-18–Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung 
Chitinase 3–like 1 (Chi3l1), which is also called YKL-40 in humans and BRP-39 in mice, is the prototypic chitinase-like protein. Recent studies have highlighted its impressive ability to regulate the nature of tissue inflammation and the magnitude of tissue injury and fibroproliferative repair. This can be appreciated in studies that highlight its induction after cigarette smoke exposure, during which it inhibits alveolar destruction and the genesis of pulmonary emphysema. IL-18 is also known to be induced and activated by cigarette smoke, and, in murine models, the IL-18 pathway has been shown to be necessary and sufficient to generate chronic obstructive pulmonary disease–like inflammation, fibrosis, and tissue destruction. However, the relationship between Chi3l1 and IL-18 has not been defined. To address this issue we characterized the expression of Chi3l1/BRP-39 in control and lung-targeted IL-18 transgenic mice. We also characterized the effects of transgenic IL-18 in mice with wild-type and null Chi3l1 loci. The former studies demonstrated that IL-18 is a potent stimulator of Chi3l1/BRP-39 and that this stimulation is mediated via IFN-γ–, IL-13–, and IL-17A–dependent mechanisms. The latter studies demonstrated that, in the absence of Chi3l1/BRP-39, IL-18 induced type 2 and type 17 inflammation and fibrotic airway remodeling were significantly ameliorated, whereas type 1 inflammation, emphysematous alveolar destruction, and the expression of cytotoxic T lymphocyte perforin, granzyme, and retinoic acid early transcript 1 expression were enhanced. These studies demonstrate that IL-18 is a potent stimulator of Chi3l1 and that Chi3l1 is an important mediator of IL-18–induced inflammatory, fibrotic, alveolar remodeling, and cytotoxic responses.
doi:10.1165/rcmb.2014-0366OC
PMCID: PMC4742933  PMID: 25955511
Chi3l1; IL-18; airway fibrosis; alveolar remodeling; COPD
10.  Regulation of Retinoic Acid Receptor Beta by Interleukin-15 in the Lung during Cigarette Smoking and Influenza Virus Infection 
Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. IL-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long-term CS exposure or influenza virus infection alone, which is further attenuated during infection after CS exposure. RA receptor β (RARβ) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARβ is found in these mice compared with wild-type (WT) mice after infection. RARβ is increased in IL-15 knockout (IL-15KO) mice compared with WT mice after infection, and the additive effect of CS and virus on RARβ down-regulation is diminished in IL-15KO mice. IL-15 receptor α (IL-15Rα) is increased and RARβ is significantly decreased in lung interstitial macrophages from IL-15Tg mice compared with WT mice. In vitro studies show that IL-15 down-regulates RARβ in macrophages via IL-15Rα signaling during influenza virus infection. These studies suggest that RA signaling is significantly diminished in the lung by CS exposure and influenza virus infection. IL-15 specifically down-regulates RARβ expression, and RARβ may play a protective role in lung injury caused by CS exposure and viral infections.
doi:10.1165/rcmb.2014-0448OC
PMCID: PMC4742936  PMID: 25923039
IL-15; chronic obstructive pulmonary disease; retinoic acid receptor; cigarette smoke; influenza
12.  IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses 
Nature Communications  2016;7:12752.
Recent studies demonstrated that chitinase 3-like-1 (Chi3l1) binds to and signals via IL-13Rα2. However, the mechanism that IL-13Rα2 uses to mediate the effects of Chi3l1 has not been defined. Here, we demonstrate that the membrane protein, TMEM219, is a binding partner of IL-13Rα2 using yeast two-hybrid, co-immunoprecipitation, co-localization and bimolecular fluorescence complementation assays. Furthermore, fluorescence anisotropy nanodisc assays revealed a direct physical interaction between TMEM219 and IL-13Rα2-Chi3l1 complexes. Null mutations or siRNA silencing of TMEM219 or IL-13Rα2 similarly decreased Chi3l1-stimulated epithelial cell HB-EGF production and macrophage MAPK/Erk and PKB/Akt activation. Null mutations of TMEM219 or IL-13Rα2 also phenocopied one another as regards the ability of Chi3l1 to inhibit oxidant-induced apoptosis and lung injury, promote melanoma metastasis and stimulate TGF-β1. TMEM219 also contributed to the decoy function of IL-13Rα2. These studies demonstrate that TMEM219 plays a critical role in Chi3l1-induced IL-13Rα2 mediated signalling and tissue responses.
Chitinase 3-like 1 regulates cell death, inflammation and tissue remodelling via IL-13receptorα2. Here, the authors show that TMEM219 is a IL-13Rα2 co-receptor and modulates oxidant-induced apoptosis and lung injury, melanoma metastasis and TGF-β1 signalling, downstream of Chi3l1-IL-13Rα2.
doi:10.1038/ncomms12752
PMCID: PMC5027616  PMID: 27629921
13.  RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis 
Scientific Reports  2016;6:26299.
Chi3l1 is induced by a variety of cancers where it portends a poor prognosis and plays a key role in the generation of metastasis. However, the mechanisms that Chi3l1 uses to mediate these responses and the pathways that control Chi3l1-induced tumor responses are poorly understood. We characterized the mechanisms that Chi3l1 uses to foster tumor progression and the ability of the RIG-like helicase (RLH) innate immune response to control Chi3l1 elaboration and pulmonary metastasis. Here we demonstrate that RLH activation inhibits tumor induction of Chi3l1 and the expression of receptor IL-13Rα2 and pulmonary metastasis while restoring NK cell accumulation and activation, augmenting the expression of IFN-α/β, chemerin and its receptor ChemR23, p-cofilin, LIMK2 and PTEN and inhibiting BRAF and NLRX1 in a MAVS-dependent manner. These studies demonstrate that Chi3l1 is a multifaceted immune stimulator of tumor progression and metastasis whose elaboration and tissue effects are abrogated by RLH innate immune responses.
doi:10.1038/srep26299
PMCID: PMC4873814  PMID: 27198666
14.  Role of Chitinase 3-like-1 and Semaphorin 7a in Pulmonary Melanoma Metastasis 
Cancer research  2014;75(3):487-496.
The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge we investigated the production of Chi3l1 in melanoma lung metastases. We found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its β1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL-13Rα2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. We confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells. Taken together, our studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL-13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.
doi:10.1158/0008-5472.CAN-13-3339
PMCID: PMC4321965  PMID: 25511377
Chi3l1; IL-13Rα2; melanoma; Lung metastasis; plexin C1; β1 integrin
15.  Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease 
The Journal of Clinical Investigation  2015;125(8):3178-3192.
Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3–like–1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Rα2 as a consequence of dysfunctional BLOC-3–dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS.
doi:10.1172/JCI79792
PMCID: PMC4563747  PMID: 26121745
16.  Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9 
Oncotarget  2015;6(34):36535-36550.
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.
PMCID: PMC4742194  PMID: 26431492
mammalian chitinase; colitis-associated cancer; bone marrow chimeras; RAGE; intestinal epithelial cells
17.  Suppression of NLRX1 in chronic obstructive pulmonary disease 
The Journal of Clinical Investigation  2015;125(6):2458-2462.
Cigarette smoke (CS) and viruses promote the inflammation and remodeling associated with chronic obstructive pulmonary disease (COPD). The MAVS/RIG-I–like helicase (MAVS/RLH) pathway and inflammasome-dependent innate immune pathways are important mediators of these responses. At baseline, the MAVS/RLH pathway is suppressed, and this inhibition must be reversed to engender tissue effects; however, the mechanisms that mediate activation and repression of the pathway have not been defined. In addition, the regulation and contribution of MAVS/RLH signaling in CS-induced inflammation and remodeling responses and in the development of human COPD remain unaddressed. Here, we demonstrate that expression of NLRX1, which inhibits the MAVS/RLH pathway and regulates other innate immune responses, was markedly decreased in 3 independent cohorts of COPD patients. NLRX1 suppression correlated directly with disease severity and inversely with pulmonary function, quality of life, and prognosis. In murine models, CS inhibited NLRX1, and CS-induced inflammation, alveolar destruction, protease induction, structural cell apoptosis, and inflammasome activation were augmented in NLRX1-deficient animals. Conversely, MAVS deficiency abrogated this CS-induced inflammation and remodeling. Restoration of NLRX1 in CS-exposed animals ameliorated alveolar destruction. These data support a model in which CS-dependent NLRX1 inhibition facilitates MAVS/RHL activation and subsequent inflammation, remodeling, protease, cell death, and inflammasome responses.
doi:10.1172/JCI71747
PMCID: PMC4497738  PMID: 25938787
Inflammation; Pulmonology
18.  Cigarette smoke-induced lung endothelial apoptosis and emphysema is associated with impairment of FAK and eIF2α 
Microvascular research  2014;94:80-89.
Lung endothelial cell (EC) apoptosis has been implicated in the pathogenesis of emphysema. However, the mechanism underlying cigarette smoke (CS)-induced lung EC apoptosis and emphysema is not well defined. We have previously shown that cigarette smoke extract (CSE) decreased focal adhesion kinase (FAK) activity via oxidative stress in cultured lung EC. In this study, we compared FAK activation in the lungs of highly susceptible AKR mice and mildly susceptible C57BL/6 mice after exposure to CS for three weeks. We found that three weeks of CS exposure caused mild emphysema and increased lung EC apoptosis in AKR mice (room air: 12.8±5.6%; CS: 30.7±3.7%), but not in C57BL/6 mice (room air: 0±0%; CS: 3.5±1.7%). Correlated with increased lung EC apoptosis and early onset of emphysema, FAK activity was reduced in the lungs of AKR mice, but not in C57BL/6 mice. Additionally, inhibition of FAK caused lung EC apoptosis, whereas over-expression of FAK prevented CSE-induced lung EC apoptosis. These results suggest that FAK inhibition may contribute to CS-induced lung EC apoptosis and emphysema. Unfolded protein response (UPR) and autophagy have been shown to be activated by CS exposure in lung epithelial cells. In this study, we noted that CSE activated UPR and autophagy in cultured lung EC, as indicated by enhanced eIF2α phosphorylation and elevated levels of GRP78 and LC3B-II. However, eIF2α phosphorylation was significantly reduced by three-weeks of CS exposure in the lungs of AKR mice, but not of C57BL/6 mice. Markers for autophagy activation were not significantly altered in the lungs of either AKR or C57BL/6 mice. These results suggest that CS-induced impairment of eIF2α signaling may increase the susceptibility to lung EC apoptosis and emphysema. Taken together, our data suggest that inhibition of eIF2α and FAK signaling may play an important role in CS-induced lung EC apoptosis and emphysema.
doi:10.1016/j.mvr.2014.05.003
PMCID: PMC4185927  PMID: 24853558
19.  Epithelial Cell Mitochondrial Dysfunction and PINK1 Are Induced by Transforming Growth Factor- Beta1 in Pulmonary Fibrosis 
PLoS ONE  2015;10(3):e0121246.
Background
Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis.
Methods
We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis.
Results
Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis.
Conclusion
TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis.
doi:10.1371/journal.pone.0121246
PMCID: PMC4364993  PMID: 25785991
20.  Chitinase 3–like 1 Suppresses Injury and Promotes Fibroproliferative Responses in Mammalian Lung Fibrosis 
Science translational medicine  2014;6(240):240ra76.
Epithelial injury, alternative macrophage accumulation, and fibroproliferation coexist in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Chitinase 3–like 1 (CHI3L1) is a prototypic chitinase-like protein that has been retained over species and evolutionary time. However, the regulation of CHI3L1 in IPF and its ability to regulate injury and/or fibroproliferative repair have not been fully defined. We demonstrated that CHI3L1 levels were elevated in patients with IPF. High levels of CHI3L1 are associated with progression—as defined by lung transplantation or death—and with scavenger receptor–expressing circulating monocytes in an ambulatory IPF population. In preterminal acute exacerbations of IPF, CHI3L1 levels were reduced and associated with increased levels of apoptosis. We also demonstrated that in bleomycin-treated mice, CHI3L1 expression was acutely and transiently decreased during the injury phase and returned toward and eventually exceeded baseline levels during the fibrotic phase. In this model, CHI3L1 played a protective role in injury by ameliorating inflammation and cell death, and a profibrotic role in the repair phase by augmenting alternative macrophage activation, fibroblast proliferation, and matrix deposition. Using three-dimensional culture system of a human fibroblast cell line, we found that CHI3L1 is sufficient to induce low grade myofibroblast transformation. In combination, these studies demonstrate that CHI3L1 is stimulated in IPF, where it represents an attempt to diminish injury and induce repair. They also demonstrate that high levels of CHI3L1 are associated with disease progression in ambulatory patients and that a failure of the CHI3L1 antiapoptotic response might contribute to preterminal disease exacerbations.
doi:10.1126/scitranslmed.3007096
PMCID: PMC4340473  PMID: 24920662
21.  Chitinase 1 Is a Biomarker for and Therapeutic Target in Scleroderma-Associated Interstitial Lung Disease That Augments TGF-β1 Signaling 
Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1−/− mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β–induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling.
doi:10.4049/jimmunol.1201115
PMCID: PMC4336775  PMID: 22826322
22.  Role of RNase L in Viral PAMP/Influenza Virus and Cigarette Smoke-induced Inflammation and Remodeling 
Interactions between cigarette smoke (CS) exposure and viral infection play an important role(s) in the pathogenesis of chronic obstructive pulmonary disease (COPD) and a variety of other disorders. A variety of lines of evidence suggest that this interaction induces exaggerated inflammatory, cytokine and tissue remodeling responses. We hypothesized that the 2′-5′OAS/RNase L system, an innate immune antiviral pathway, plays an important role in the pathogenesis of these exaggerated responses. To test this hypothesis we characterize the activation of 2′-5′ oligoadenylate synthase (OAS) in lungs from mice exposed to CS and viral PAMPs/live virus, alone and in combination. We also evaluated the inflammatory and remodeling responses induced by CS and virus/viral PAMPs in lungs from RNase L null and wild type mice. These studies demonstrate that CS and viral PAMPs/live virus interact in a synergistic manner to stimulate the production of select OAS moieties. They also demonstrate that RNase L plays a critical role in the pathogenesis of the exaggerated inflammatory, fibrotic, emphysematous, apoptotic, TGF-β1 and type I IFN responses induced by CS plus virus/viral PAMP in combination. These studies demonstrate that CS is an important regulator of antiviral innate immunity, highlight novel roles of RNase L in CS plus virus induced inflammation, tissue remodeling, apoptosis and cytokine elaboration and highlight pathways that may be operative in COPD and mechanistically-related disorders.
doi:10.4049/jimmunol.1300082
PMCID: PMC3750064  PMID: 23913960
23.  Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2 
Cell reports  2013;4(4):830-841.
SUMMARY
Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.
doi:10.1016/j.celrep.2013.07.032
PMCID: PMC3988532  PMID: 23972995
24.  Chitinase 3-like 1 is induced by Plasmodium falciparum malaria and predicts outcome of cerebral malaria and severe malarial anaemia in a case–control study of African children 
Malaria Journal  2014;13:279.
Background
Severe and fatal malaria are associated with dysregulated host inflammatory responses to infection. Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein implicated in regulating immune responses. Expression and function of CHI3L1 in malaria infection were investigated.
Methods
Plasma levels of CHI3L1 were quantified in a case–control study of Ugandan children presenting with Plasmodium falciparum malaria. CHI3L1 levels were compared in children with uncomplicated malaria (UM; n = 53), severe malarial anaemia (SMA; n = 59) and cerebral malaria (CM; n = 44) using the Kruskall Wallis-test, and evaluated for utility in predicting fatal (n = 23) versus non-fatal (n = 80) outcomes in severe disease using the Mann Whitney U test, receiver operating characteristic curves, and combinatorial analysis. Co-culture of P. falciparum with human peripheral blood mononuclear cells and the Plasmodium berghei ANKA experimental model of cerebral malaria were used to examine the role of CHI3L1 in severe malaria.
Results
In children presenting with falciparum malaria, CHI3L1 levels were increased in SMA and CM versus UM (p < 0.001). Among severe malaria cases, CHI3L1 levels at presentation predicted subsequent death (area under receiver operating characteristic curve 0.84 [95% CI 0.76-0.92]) and in combination with other host biomarkers, predicted mortality with high sensitivity (100% [85.7-100]) and specificity (81.3% [71.3-88.3]). Plasmodium falciparum stimulated CHI3L1 production by human peripheral blood mononuclear cells in vitro. CHI3L1 was increased in plasma and brain tissue in experimental cerebral malaria, but targeted Chi3l1 deletion did not alter cytokine production or survival in this model.
Conclusions
These data suggest that plasma CHI3L1 measured at presentation correlates with malaria severity and predicts outcome in paediatric SMA and CM, but do not support a causal role for CHI3L1 in cerebral malaria pathobiology in the model tested.
doi:10.1186/1475-2875-13-279
PMCID: PMC4114103  PMID: 25047113
Cerebral malaria; Severe malaria; Chitinase 3-like 1; CHI3L1; Biomarker; Pathogenesis; Inflammation
25.  VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis 
The Journal of Experimental Medicine  2013;210(10):1993-2010.
VEGF dampens the expression of microRNA-1, which drives inflammation in part via increasing the expression of Mpl.
Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF–miR-1–Mpl–P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.
doi:10.1084/jem.20121200
PMCID: PMC3782056  PMID: 24043765

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