RON RECEPTOR TYROSINE KINASE NEGATIVELY REGULATES TNFα PRODUCTION IN ALVEOLAR MACROPHAGES BY INHIBITING NF-κB ACTIVITY AND ADAM17 PRODUCTION

Nikolaidis, Nikolaos M.; Gray, Jerilyn K.; Gurusamy, Devikala; Fox, William P.; Stuart, William D.; Huber, Nathan L.; Waltz, Susan E.

doi:10.1097/shk.0b013e3181ae8155

Cited by 38 publications

(54 citation statements)

References 35 publications

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“…Consistent with these in vivo data, ex vivo LPS treatment of TKϪ/Ϫ BMDMs led to significant increases in TNF-␣, iNOS, and IL-6 expression compared with TKϩ/ϩ cells. These studies are in accord with numerous publications citing the macrophage-specific regulation of cytokines and iNOS expression by Ron in vivo and in vitro (23,28,29,34,43). Macrophages play a vital role in inflammation, and their activation status determines the repertoire of proinflammatory or anti-inflammatory cytokine production.…”

Section: Discussionsupporting

confidence: 85%

Ron receptor signaling is protective against DSS-induced colitis in mice

Kulkarni

Stuart

Gurusamy

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestine that result in painful and debilitating complications. Currently no cure exists for IBD, and treatments are primarily aimed at reducing inflammation to alleviate symptoms. Genome-wide linkage studies have identified the Ron receptor tyrosine kinase (TK) and its ligand, hepatocyte growth factor-like protein (HGFL), as genes highly associated with IBD. However, only scant information exists on the role of Ron or HGFL in IBD. Based on the linkage of Ron to IBD, we directly examined the biological role of Ron in colitis. Wild-type mice and mice lacking the TK signaling domain of Ron (TK-/- mice) were utilized in a well-characterized model of chronic colitis induced by cyclic exposure to dextran sulfate sodium. In this model, TK-/- mice were more susceptible to injury as judged by increased mortality compared with control mice and developed more severe colitis. Loss of Ron led to significantly reduced body weights and more aggressive clinical and histopathologies. Ron loss also resulted in a dramatic reduction in colonic epithelial cell proliferation and increased proinflammatory cytokine production, which was associated with alterations in important signaling pathways known to regulate IBD. Examination of human gene expression data further supports the contention that loss of Ron signaling is associated with IBD. In total, our studies point to important functional roles for Ron in IBD by regulating healing of the colonic epithelium and by controlling cytokine secretion.

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Section: Discussionsupporting

confidence: 85%

Ron receptor signaling is protective against DSS-induced colitis in mice

Kulkarni

Stuart

Gurusamy

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…23,35 TAMs were reported to suppress anti-tumor CD8 + T-cell responses in a mouse model of prostate cancer via RON signaling. 35 On the other hand, RON can also attenuate inflammatory responses in alveolar macrophages and protect mice from mortality following lung injury, 30 suggesting potent control of the immune responses in a localized manner. Supporting this view, local expression of MSP by breast cancer cells has been shown to recruit TAMs and polarize them into an immunosuppressive phenotype, resulting in enhanced tumor growth in mice.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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“…Several studies have demonstrated that the RON receptor inhibits LPS and cytokine-induced NF-κB activation in a variety of macrophage populations (6, 15, 16); however, the molecular targets of Ron downstream of TLR activation in primary macrophages have not been systematically addressed. In this report, we show that stimulation of primary peritoneal macrophages with MSP, the ligand for Ron, does not inhibit receptor proximal signaling events initiated by LPS stimulation of TLR4, but rather specifically inhibits the activation of IκB kinase (IKK) and its downstream targets by LPS.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of TLR4-Induced IκB Kinase Activity by the RON Receptor Tyrosine Kinase and Its Ligand, Macrophage-Stimulating Protein

Ray

Yu²,

Sharda

et al. 2010

The Journal of Immunology

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The RON receptor tyrosine kinase regulates the balance between classical (M1) and alternative (M2) macrophage activation. In primary macrophages, the ligand for Ron, macrophage-stimulating protein (MSP), inhibits the expression of inducible NO synthase, a marker of classically activated macrophages, whereas promoting the expression of arginase I, a marker of alternative activation. Ron−/− mice express increased levels of IL-12, a product of classically activated macrophages, after endotoxin administration, resulting in increased serum IFN-γ levels and enhanced susceptibility to septic shock. In this study, we demonstrate that MSP inhibits LPS-induced IL-12p40 expression, and this inhibition is dependent on the docking site tyrosines in Ron. To further define this inhibition, we examined the effect of Ron on signaling pathways downstream of Ron. We found that MSP does not inhibit the MyD88-independent activation of IFN regulatory factor 3 and production of IFN-β in response to LPS, nor does it inhibit MyD88-dependent TGF-β–activated kinase phosphorylation or MAPK activation in primary macrophages. However, the induction of IκB kinase activity, IκB degradation, and DNA binding of NF-κB after LPS stimulation is delayed in the presence of MSP. In addition, Ron inhibits serine phosphorylation of p65 and NF-κB transcriptional activity induced by LPS stimulation of TLR4. Finally, MSP inhibits the NF-κB–dependent upregulation of the nuclear IκB family member, IκBζ, a positive regulator of secondary response genes including IL-12p40. LPS also induces expression of Ron and an N-terminally truncated form of Ron, Sf-Ron, in primary macrophages, suggesting that the upregulation of Ron by LPS could provide classical feedback regulation of TLR signaling.

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RON RECEPTOR TYROSINE KINASE NEGATIVELY REGULATES TNFα PRODUCTION IN ALVEOLAR MACROPHAGES BY INHIBITING NF-κB ACTIVITY AND ADAM17 PRODUCTION

Cited by 38 publications

References 35 publications

Ron receptor signaling is protective against DSS-induced colitis in mice

Ron receptor signaling is protective against DSS-induced colitis in mice

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Inhibition of TLR4-Induced IκB Kinase Activity by the RON Receptor Tyrosine Kinase and Its Ligand, Macrophage-Stimulating Protein

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