Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

Lee, Ye Ji; Lee, Seung Hae; Youn, Young So; Choi, Ji Yeon; Song, Keung Sub; Cho, Min Sun; Kang, Jihee Lee

doi:10.1016/j.taap.2012.05.024

Cited by 29 publications

(29 citation statements)

References 50 publications

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“…1 ) is therefore an important fi nding, particularly as other receptors in addition to CD36 are likely involved and may have been predicted to obscure any effects of CD36 defi ciency (i.e., make CD36 functionally redundant in this model) ( 2 ). Indeed, similar effects on efferocytosis and lung infl ammation were recently reported for the MER tyrosine kinase receptor in mice following bleomycin-induced lung injury ( 39 ). The modulatory effects of CD36 on subsequent infl ammatory and fi brotic events also reveal the importance of this receptor in regulating processes that are pathophysiologically relevant to idiopathic pulmonary fi brosis (IPF).…”

Section: Discussionsupporting

confidence: 55%

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

Parks

Black

Zimmerman

et al. 2013

Journal of Lipid Research

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Section: Discussionsupporting

confidence: 55%

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

Parks

Black

Zimmerman

et al. 2013

Journal of Lipid Research

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“…The isotype antibody had no effects. As described previously elsewhere (Lee et al, 2012b), anti-Mer antibody without TAPI-0 suppressed downstream signaling of Mer, and enhanced NF-kB signaling, the production of these proinflammatory mediators, accumulation of inflammatory cells, and the total protein levels in BAL fluid compared with control (the LPS group). However, the inhibitory effects of anti-Mer with TAPI-0 were greater than those of anti-Mer without TAPI-0.…”

Section: Tapi-0 Treatment Reduces Smer Production Andmentioning

confidence: 62%

“…Using specific anti-Mer neutralizing antibodies, our data previously had indicated that the downregulation effect of TAPI-0 on sustained lung inflammation after bleomycin treatment was mediated by increased activation of Mer (Lee et al, 2012b). An important distinction between the models of bleomycin and LPS-induced lung injury is the sequence and magnitude of the inflammatory events as well as the healing response.…”

Section: Upregulation Of Mer Attenuated Lung Inflammationmentioning

confidence: 99%

“…Within 24 hours of intratracheal bleomycin administration, there is an increase in BAL neutrophils, which then normalize toward day 11 (Matute-Bello et al, 2008). Proinflammatory cytokines peak between 24 and 72 hours (Serrano-Mollar et al, 2003;Lee et al, 2012b). The fibrotic response persists by days 14-28 (Shen et al, 1988).…”

Section: Upregulation Of Mer Attenuated Lung Inflammationmentioning

confidence: 99%

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Upregulation of Mer Receptor Tyrosine Kinase Signaling Attenuated Lipopolysaccharide-Induced Lung Inflammation

Choi¹,

Park²,

Lee³

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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Mer receptor tyrosine kinase (Mer) signaling plays a central role in the intrinsic inhibition of the inflammatory response to Tolllike receptor activation. Previously, we found that lung Mer protein expression decreased after lipopolysaccharide (LPS) treatment due to enhanced Mer cleavage. The purpose of the present study was to examine whether pharmacologically restored membrane-bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses. Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS-induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane-bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment. TAPI-0 also enhanced Mer downstream signaling, including phosphorylation of protein kinase b, focal adhesion kinase, and signal transducer and activator of transcription 1. As expected from enhanced Mer signaling, TAPI-0 also augmented suppressor of cytokine signaling-1 and -3 mRNA and protein levels and inhibited nuclear factor kB activation at 4 and 24 hours after LPS treatment. TAPI-0 suppressed LPS-induced inflammatory cell accumulation, total protein level elevation in BAL fluid, and production of inflammatory mediators, including tumor necrosis factor-a, interleukin-1b, and macrophage inflammatory protein-2. Additionally, the effects of TAPI-0 on the activation of Mer signaling and the production of inflammatory responses could be reversed by cotreatment with specific Merneutralizing antibody. Restored Mer protein expression by treatment with TAPI-0 efficiently prevents the inflammatory cascade during acute lung injury.

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“…In mouse models of lung disease, prevention of the proteolytic cleavage of Mer led to beneficial Mer-dependent pro-phagocytic and anti-inflammatory responses [56,57]. These results in mice suggest that increasing membrane-bound Mer activation may also have a beneficial effect in SLE.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of Mer tyrosine kinase in circulating dendritic cells and monocytes of lupus patients: correlations with plasma interferon activity and steroid therapy

et al. 2014

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IntroductionThe requirement for the immunoregulatory Mer tyrosine kinase (Mer) for optimal removal of apoptotic cells prompted us to look at its expression in systemic lupus erythematosus (SLE), in which apoptotic cell clearance is abnormal. We compared the levels of expression of Mer in normal human subjects and in patients with SLE.MethodsWe used flow cytometry of isolated peripheral blood mononuclear cells to compare the levels of Mer on leukocyte subsets. We used a Mer-specific enzyme-linked immunosorbent assay (ELISA) to quantify soluble Mer (sMer) in plasmas.ResultsMonocytes, CD1c+ myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs) from both normal individuals and from SLE patients expressed Mer. In both normal and SLE patients, the CD14++CD16+ subpopulation of monocytes expressed the highest levels of Mer, with somewhat lower levels on the CD14intCD16+ population. Mer levels on CD1c+ mDCs and pDCs, and sMer levels in blood were increased in SLE patients compared with controls. In patients, Mer levels on CD14intCD16+, CD14++CD16- monocytes, and CD1c+ dendritic cells correlated positively with type I interferon (IFN-I) activity detected in blood. In SLE patients treated with corticosteroids, Mer expression on monocytes correlated with prednisone dose, CD1c+ myeloid dendritic cells in patients treated with prednisone had higher levels of Mer expression than those in patients not receiving prednisone.ConclusionsWe found no global defect in Mer expression in lupus blood. In contrast, we observed increased levels of Mer expression in DC populations, which could represent a response to increased IFN-I in SLE patients. Enhanced Mer expression induced by corticosteroids may contribute to its beneficial effects in SLE.

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Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

Cited by 29 publications

References 50 publications

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

Upregulation of Mer Receptor Tyrosine Kinase Signaling Attenuated Lipopolysaccharide-Induced Lung Inflammation

Increased expression of Mer tyrosine kinase in circulating dendritic cells and monocytes of lupus patients: correlations with plasma interferon activity and steroid therapy

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