title: Matrix protein CCN1 induced by bacterial DNA and CpG ODN limits lung inflammation and contributes to innate immune homeostasis.
abstract: To defend against pulmonary infections, lung epithelial cells are equipped with complex innate immunity closely linked to inflammation. Dysregulated innate immunity/inflammation leads to self-perpetuating lung injury. The CpG motif in bacterial DNA is one of the factors involved in bacterial infection-associated inflammation. Bacterial DNA and synthetic CpG oligonucleotide (ODN) induced CCN1 secretion from lung epithelial cells, functioning as a potential "braking" signal to prevent uncontrolled inflammatory responses. CpG ODN-induced endoplasmic reticulum (ER) stress resulted in Src-Y527 phosphorylation (pY527) and Src/CCN1 vWF domain dissociation. Src-Y527 activated caveolin-1 (cav-1) phosphorylation at Y14 and then modulated CCN1 secretion via pCav-1 interaction with the CCN1 IGFbp domain. Functionally, secreted CCN1 promoted anti-inflammatory cytokine interleukin (IL)-10 release from epithelial cells via integrin αVβ6-PKC, and this subsequently suppressed tumor necrosis factor (TNF)-α, macrophage inflammatory protein 2 (MIP-2)-2 secretion and neutrophil infiltration in the lungs. Collectively, bacterial DNA/CpG ODN-stimulated CCN1 secretion via the BiP/GRP78-Src(Y527)-JNK-Cav-1(Y14) pathway and CpG-induced CCN1 conferred anti-inflammatory roles. Our studies suggested a novel paradigm by which the lung epithelium maintains innate immune homeostasis after bacterial infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: H-G
authors.initials: HG
authors.lastname: Moon
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: T
authors.initials: T
authors.lastname: Quan
authors.affiliation: Department of Respiratory Medicine, Chinese PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Dela Cruz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism*; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006706:Homeostasis; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010766:Phosphorylation; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000951:Antigens, Neoplasm; C408982:CPG-oligonucleotide; D051242:Caveolin 1; D055515:Cysteine-Rich Protein 61; D016207:Cytokines; D004269:DNA, Bacterial; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D018836:Inflammation Mediators; D016023:Integrins; D009838:Oligodeoxyribonucleotides; C073878:integrin alphavbeta6; D016753:Interleukin-10; D016392:Proto-Oncogene Proteins pp60(c-src)