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Mucosal Immunol. 2015 Mar;8(2):243-53. doi: 10.1038/mi.2014.62. Epub 2014 Jul 9.

Matrix protein CCN1 induced by bacterial DNA and CpG ODN limits lung inflammation and contributes to innate immune homeostasis.

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Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Respiratory Medicine, Chinese PLA General Hospital, Beijing, China.
Department of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, Connecticut, USA.


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.

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