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1.  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
2.  Role of Chitin and Chitinase/Chitinase-Like Proteins in Inflammation, Tissue Remodeling, and Injury 
Annual review of physiology  2011;73:10.1146/annurev-physiol-012110-142250.
The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitin-induced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.
doi:10.1146/annurev-physiol-012110-142250
PMCID: PMC3864643  PMID: 21054166
asthma; fibrosis; BRP-39/YKL-40; AMCase; chitotriosidase
3.  Chitinase-like Proteins in Lung Injury, Repair, and Metastasis 
This report explains how our studies of asthma and Th2 inflammation led us to investigate the roles of chitinase-like proteins (CLPs) in lung injury and repair and puts forth an overall hypothesis that can explain the roles that these moieties play in biology and a hypothesis regarding the ways that dysregulated CLP expression may contribute to the pathogenesis of a variety of diseases. We test this hypothesis by assessing the contributions of the CLP breast regression protein (BRP)-39 in the pathogenesis of malignant melanoma metastasis to the lung.
doi:10.1513/pats.201112-056MS
PMCID: PMC3359113  PMID: 22550243
BRP-39/YKL-40; inflammation; injury; repair; metastasis
4.  RIG-like Helicase Innate Immunity Inhibits Vascular Endothelial Growth Factor Tissue Responses via a Type I IFN–dependent Mechanism 
Rationale: Vascular endothelial growth factor (VEGF) regulates vascular, inflammatory, remodeling, and cell death responses. It plays a critical role in normal pulmonary physiology, and VEGF excess and deficiency have been implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease, respectively. Although viruses are an important cause of chronic obstructive pulmonary disease exacerbations and innate responses play an important role in these exacerbations, the effects of antiviral responses on VEGF homeostasis have not been evaluated.
Objectives: We hypothesized that antiviral innate immunity regulates VEGF tissue responses.
Methods: We compared the effects of transgenic VEGF165 in mice treated with viral pathogen–associated molecular pattern polyinosinic:polycytidylic acid [poly(I:C)], mice treated with live virus, and control mice.
Measurements and Main Results: Transgenic VEGF stimulated angiogenesis, edema, inflammation, and mucin accumulation. Each of these was abrogated by poly(I:C). These inhibitory effects were dose dependent, noted when poly(I:C) was administered before and after transgene activation, and mediated by a Toll-like receptor-3–independent and RIG-like helicase (RLH)– and type I IFN receptor–dependent pathway. VEGF stimulated the expression of VEGF receptor-1 and poly(I:C) inhibited this stimulation. Poly(I:C) also inhibited the ability of VEGF to activate extracellular signal–regulated kinase-1, Akt, focal adhesion kinase, and endothelial nitric oxide synthase, and aeroallergen-induced adaptive helper T-cell type 2 inflammation. Influenza and respiratory syncytial virus also inhibited VEGF-induced angiogenesis.
Conclusions: These studies demonstrate that poly(I:C) and respiratory viruses inhibit VEGF-induced tissue responses and adaptive helper T-cell type 2 inflammation and highlight the importance of a RLH- and type I IFN receptor–dependent pathway(s) in these regulatory events. They define a novel link between VEGF and antiviral and RLH innate immune responses and a novel pathway that regulates pulmonary VEGF activity.
doi:10.1164/rccm.201008-1276OC
PMCID: PMC3114061  PMID: 21278304
RIG-like helicase; mitochondrial antiviral signaling molecule; influenza virus; chronic obstructive pulmonary disease
5.  Cigarette smoke selectively enhances viral PAMP– and virus-induced pulmonary innate immune and remodeling responses in mice 
The Journal of Clinical Investigation  2008;118(8):2771-2784.
Viral infections have more severe consequences in patients who have been exposed to cigarette smoke (CS) than in those not exposed to CS. For example, in chronic obstructive pulmonary disease (COPD), viruses cause more severe disease exacerbation, heightened inflammation, and accelerated loss of lung function compared with other causes of disease exacerbation. Symptomatology and mortality in influenza-infected smokers is also enhanced. To test the hypothesis that these outcomes are caused by CS-induced alterations in innate immunity, we defined the effects of CS on pathogen-associated molecular pattern–induced (PAMP-induced) pulmonary inflammation and remodeling in mice. CS was found to enhance parenchymal and airway inflammation and apoptosis induced by the viral PAMP poly(I:C). CS and poly(I:C) also induced accelerated emphysema and airway fibrosis. The effects of a combination of CS and poly(I:C) were associated with early induction of type I IFN and IL-18, later induction of IL-12/IL-23 p40 and IFN-γ, and the activation of double-stranded RNA-dependent protein kinase (PKR) and eukaryotic initiation factor-2α (eIF2α). Further analysis using mice lacking specific proteins indicated a role for TLR3-dependent and -independent pathways as well as a pathway or pathways that are dependent on mitochondrial antiviral signaling protein (MAVS), IL-18Rα, IFN-γ, and PKR. Importantly, CS enhanced the effects of influenza but not other agonists of innate immunity in a similar fashion. These studies demonstrate that CS selectively augments the airway and alveolar inflammatory and remodeling responses induced in the murine lung by viral PAMPs and viruses.
doi:10.1172/JCI32709
PMCID: PMC2483678  PMID: 18654661

Results 1-5 (5)