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

Moon, Hyung‐Geun; Qin, Zhaoping; Quan, Taihao; Xie, Lixin; Cruz, Charles S. Dela; Jin, Yang

doi:10.1038/mi.2014.62

Cited by 16 publications

(14 citation statements)

References 52 publications

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“…We observed increased phosphorylation of SRC at both the activating site (Y416) and the inactivating site (Y527). Induction of SRC phosphorylation at both tyrosine phosphorylation sites, as well as activated SRC signaling in the absence of reduced phosphorylation at Y527, has been observed by others (45–47), and likely reflects heterogeneity among the cells. In our studies the dominant functional effect of RON was an overall increase in SRC activity, evidenced by a decrease in downstream SRC signaling after RON inhibition, and our observation that constitutively-activated SRC rescued resorption in osteoclasts lacking RON kinase activity.…”

Section: Discussionsupporting

confidence: 61%

RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis

et al. 2017

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Bone destruction occurs in aging and numerous diseases, including osteoporosis and cancer. Many cancer patients have bone osteolysis that is refractory to state-of-the-art treatments, which block osteoclast activity with bisphosphonates or by inhibiting the RANKL pathway. We previously showed that macrophage-stimulating protein (MSP) signaling, which is elevated in approximately 40% of breast cancers, promotes osteolytic bone metastasis, but it was unknown whether this was due to activation of the MSP signaling pathway in the tumor cells or in the bone microenvironment. Here we show that MSP signals through host expression of its receptor, RON tyrosine kinase, to directly activate osteoclasts by a previously undescribed pathway that is complementary to RANKL signaling and converges on SRC. Genetic or pharmacologic inhibition of RON kinase blocked cancer-mediated bone destruction and osteoporosis in several mouse models. Furthermore, the RON kinase inhibitor BMS-777607/ASLAN002 altered markers of bone turnover in a first-in-human clinical cancer study, indicating potential for normalizing bone loss in patients. These findings uncover a new therapeutic target for pathogenic bone loss and provide a rationale for treatment of bone destruction in various diseases with RON inhibitors.

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Section: Discussionsupporting

confidence: 61%

RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis

et al. 2017

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“…Another study suggested that CpG can induce CCN1 secretion and IL-10 release from lung epithelial cells by the BiP/GRP78-Src(Y527)-JNK-Cav-1(Y14) pathway, which can suppress TNF-α, macrophage inflammatory protein 2 (MIP-2) secretion and neutrophil infiltration in the lungs. 18 In addition, CpG can protect human monocytic cells against HIV-viral protein R (Vpr) induced apoptosis by the calcium-activated JNK pathway in a TLR9-independent manner. 24 Although pathogenesis and pathological mechanism of periodontitis are different from those diseases, these studies provide us reasons for further investigating the underlying TLR9-independent mechanism of CpG in periodontitis.…”

Section: Discussionmentioning

confidence: 99%

Cytidine-phosphate-guanosine oligodeoxynucleotides in combination with CD40 ligand decrease periodontal inflammation and alveolar bone loss in a TLR9-independent manner

Zhao

Hu²,

Deng³

et al. 2018

J. Appl. Oral Sci.

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Local administration of toll-like receptor 9 (TLR9), agonist cytidine-phosphate-guanosine oligodeoxynucleotide (CpG ODNs), and CD40 ligand (CD40L) can decrease ligature-induced periodontal inflammation and bone loss in wild type (WT) mouse.Objective:This study aimed to explore whether such effect is dependent on TLR9 signaling.Material and Methods:Purified spleen B cells isolated from WT C57BL/6J mice and TLR9 knockout (KO) mice were cultured for 48 hours under the following conditions: CD40L, CpG+CD40L, CpG at low, medium and high doses. We determined B cell numbers using a hemocytometer at 24 h and 48 h. Percentages of CD1dhiCD5+ B cells were detected by flow cytometry. Interleukin-10 (IL-10) mRNA expression and protein secretion were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and by ELISA, respectively. The silk ligature was tied around the maxillary second molars for 14 days, during which the CpG+CD40L mixture or PBS was injected into palatal gingiva on days 3, 6, and 9.Results:For both WT and TLR9 KO mice, CpG significantly induced B cell proliferation, increased IL-10 mRNA expression and protein secretion of IL-10 but reduced CD1dhiCD5+ B cells population; local injection of CpG+CD40L mixture significantly decreased alveolar bone loss and the number of TRAP-positive cells adjacent to the alveolar bone surface, and significantly increased the gingival mRNA expression of IL-10 and decreased RANKL and IFN-γ mRNA expression.Conclusions:These results indicated that CpG plus CD40L decreased periodontal inflammation and alveolar bone loss in a TLR9-independent manner in ligature-induced experimental periodontitis.

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“…For example, Moon et al have reported that endogenous lung epithelial cell-produced CCN1 exerted anti-inflammatory activity by promoting IL-10 production and by inhibiting multiple pro-inflammatory cytokines and neutrophil infiltration into the lung (25). Further, Jin et al demonstrated that suppressing CCN1 expression by siRNA accelerated lung epithelial cell death after hyperoxia, and conversely that overexpressing CCN1, conferred increased resistance to hyperoxia-induced cell death (26).…”

Section: Discussionmentioning

confidence: 99%

Recombinant CCN1 prevents hyperoxia-induced lung injury in neonatal rats

et al. 2017

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Background Cystein rich protein 61 (Cyr61/CCN1) is a member of the CCN family of matricellular proteins that plays an improtant role in tissue development and remodeling. However, the role of CCN1 in in the pathogensis of bronchopulmonary dysplasia (BPD) is unknown. Accordingly, we have investigated the effects of CCN1 on a hyperoxia-induced lung injury model in neonatal rats. Methods In experiment 1: newborn rats were randomized to room air (RA) or 85% oxygen (O2) for 7 or 14 days and we assessed the expression of CCN1. In experiment 2: rat pups were exposed to RA or O2 and received placebo or recombinant CCN1 by daily ip injection for 10 days. The effects of CCN1 on hyperoxia-induced lung inflammation, alveolar and vascular development, vascular remodeling, and right ventricular hypertrophy (RVH). Main Results In experiment 1, hyperoxia down-regulated CCN1 expression. In experiment 2, treatment with recombinant CCN1 significantly decreased macrophage and neutrophil infiltration, reduced inflammasome activiation, increased alveolar and vascular development, reduced vascular remodeling and RVH in the hyperoxic animals. Conclusion These results demonstrate that hyperoxia-induced lung injury is associated with down-regulated basal CCN1 expression, and treatment with CCN1 can largely reverse hyperoxic injury.

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

Cited by 16 publications

References 52 publications

RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis

RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis

Cytidine-phosphate-guanosine oligodeoxynucleotides in combination with CD40 ligand decrease periodontal inflammation and alveolar bone loss in a TLR9-independent manner

Recombinant CCN1 prevents hyperoxia-induced lung injury in neonatal rats

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