RESUMO
Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithelial cells of MyD88/Trif-deficient mice express diminished levels of the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG), and systemic lipopolysaccharide administration induces their expression in the colon. N-ethyl-N-nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfr both produce a strong DSS colitis phenotype, and the Adam17 mutation exerts its deleterious effect in the nonhematopoietic compartment. The effect of abrogation of TLR signaling is mitigated by systemic administration of AREG. A TLRâMyD88âAREG/EREGâEGFR signaling pathway is represented in nonhematopoietic cells of the intestinal tract, responds to microbial stimuli once barriers are breached, and mediates protection against DSS-induced colitis.
Assuntos
Colite/prevenção & controle , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Glicoproteínas/metabolismo , Sistema Hematopoético/citologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Anfirregulina , Animais , Colite/induzido quimicamente , Colite/metabolismo , Sulfato de Dextrana , Família de Proteínas EGF , Epirregulina , Ligantes , Lipopolissacarídeos/farmacologia , Metagenoma/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Fator 88 de Diferenciação Mieloide/deficiência , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismoRESUMO
The lectin pathway of complement is activated when a carbohydrate recognition complex and associated serine proteases binds to the surface of a pathogen. Three recognition subcomponents have been shown to form active initiation complexes: mannan-binding lectin (MBL), L-ficolin, and H-ficolin. The importance of MBL in antimicrobial host defense is well recognized, but the role of the ficolins remains largely undefined. This report shows that L-ficolin specifically binds to lipoteichoic acid (LTA), a cell wall component found in all Gram-positive bacteria. Immobilized LTA from Staphylococcus aureus binds L-ficolin complexes from sera, and these complexes initiate lectin pathway-dependent C4 turnover. C4 activation correlates with serum L-ficolin concentration, but not with serum MBL levels. L-ficolin binding and corresponding levels of C4 turnover were observed on LTA purified from other clinically important bacteria, including Streptococcus pyogenes and Streptococcus agalactiae. None of the LTA preparations bound MBL, H-ficolin, or the classical pathway recognition molecule, C1q.