Extracellular Matrix Lumican Promotes Bacterial Phagocytosis, and Lum−/− Mice Show Increased Pseudomonas aeruginosa Lung Infection Severity

Shao, Han; Lee, Seakwoo; Gae-Scott, Sherri; Nakata, Chiaki; Chen, Shoujun; Hamad, Abdel Rahim A.; Chakravarti, Shukti

doi:10.1074/jbc.m112.380550

Cited by 43 publications

(37 citation statements)

References 47 publications

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“…For all donors, lumican significantly promoted fibrocyte differentiation from isolated monocytes with an EC 50 of 1.8 ± 0.9 μg/mL and a Hill coefficient of 2.9 ± 0.9 (mean ± SEM, n = 3). The EC 50 and Hill coefficient for monocytes were not significantly different from those of PBMC (t tests). These data suggest that lumican acts directly on monocytes to potentiate fibrocyte differentiation.…”

Section: Significancementioning

confidence: 99%

“…S3B). The lumican EC 50 for promoting human fibrocyte differentiation was 2.9 ± 1.2 μg/mL, with a Hill coefficient of 7.4 ± 4.3 (mean ± SEM, n = 3). To determine whether lumican altered the phenotype of fibrocytes, we stained PBMC after 5 d of culture with or without lumican for collagen-I.…”

Section: Significancementioning

confidence: 99%

“…Lumican is vital for the correct formation of collagen fibrils and promotes cell adhesion and migration (40,(45)(46)(47). Lumican knockout mice have multiple defects, including corneal opacity, skin and tendon fragility, and defective leukocyte migration (46,(48)(49)(50)(51).…”

Section: Significancementioning

confidence: 99%

“…Lumican is present in human and murine lungs, and serum lumican levels are increased following lung inflammation and asthma (50,60,61). To determine whether lung lumican levels are up-regulated in pulmonary fibrosis, we stained lung tissue from mice that aspirated bleomycin or saline.…”

Section: Lung Lumican Levels Increase In a Mouse Model Of Pulmonary Fmentioning

confidence: 99%

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TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

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Vakil

Cox

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

103

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In healing wounds and fibrotic lesions, fibroblasts and monocyte-derived fibroblast-like cells called fibrocytes help to form scar tissue. Although fibrocytes promote collagen production by fibroblasts, little is known about signaling from fibroblasts to fibrocytes. In this report, we show that fibroblasts stimulated with the fibrocyte-secreted inflammatory signal tumor necrosis factor-α secrete the small leucine-rich proteoglycan lumican, and that lumican, but not the related proteoglycan decorin, promotes human fibrocyte differentiation. Lumican competes with the serum fibrocyte differentiation inhibitor serum amyloid P, but dominates over the fibroblast-secreted fibrocyte inhibitor Slit2. Lumican acts directly on monocytes, and unlike other factors that affect fibrocyte differentiation, lumican has no detectable effect on macrophage differentiation or polarization. α2β1, αMβ2, and αXβ2 integrins are needed for lumican-induced fibrocyte differentiation. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, lumican is present at low levels throughout the tissue, whereas patients with advanced disease have pronounced lumican expression in the fibrotic lesions. These data may explain why fibrocytes are increased in fibrotic tissues, suggest that the levels of lumican in tissues may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and indicate that modulating lumican signaling may be useful as a therapeutic for fibrosis.

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Lung Lumican Levels Increase In a Mouse Model Of Pulmonary Fmentioning

confidence: 99%

See 2 more Smart Citations

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

Pilling

Vakil

Cox

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

103

View full text Add to dashboard Cite

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“…224,225 However, unlike the SLRP biglycan which acts as an endogenous ligand for TLR4 and TLR2, 226 lumican appears to have an indirect effect on receptormediated signaling by presenting other ligands to their respective receptors. Interestingly, lumican mediates interaction between LPS and CD14, thereby activating the TLR4 pathway in macrophages.…”

Section: The Multiple Roles Of Syndecan-4 In Cardiac Remodelingmentioning

confidence: 99%

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

et al. 2013

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Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan‐4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan‐4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide through the toll‐like receptor‐4, induced syndecan‐4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor‐κB transcription factor in the syndecan‐4 promoter, and nuclear factor‐κB regulated syndecan‐4 mRNA in cardiac cells. Interestingly, tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide induced nuclear factor‐κB‐dependent shedding of the syndecan‐4 ectodomain from cardiac cells. Overexpression of syndecan‐4 with mutated enzyme‐interacting domains suggested enzyme‐dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation‐induced shedding affects function. After aortic banding, a time‐dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan‐4 knockout hearts. Finally, syndecan‐4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan‐4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.

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Lumican negatively controls the pathogenicity of murine encephalitic TH17 cells

et al. 2016

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TH17 cells play an essential role in the development of both human multiple sclerosis and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, it is not well understood how the pathogenicity of TH17 cells is controlled in the autoimmune neuro-inflammation. In vitro, we found Lumican (Lum), an extracellular matrix protein, is selectively expressed by TH17 cells among tested murine TH subsets. Lum-deficiency leads to earlier onset and enhanced severity of experimental autoimmune encephalomyelitis. This enhanced disease in Lum-deficient mice is associated with increased production of IL-17 and IL-21 and decreased TH17 cell apoptosis. Dysregulation in cytokine production appears to be specific to TH17 cells as TH1 and TH2 cell polarization and/or cytokine production were unaltered. Furthermore, adoptive transfer of MOG-specific TH17 cells derived from Lum-deficient mice led to earlier onset and increased severity of disease compared to controls highlighting a TH17 cell-intrinsic effect of Lum. Taken together, our results suggest that Lum negatively regulates encephalitic TH17 cells, implicating a potential therapeutic pathway in TH17 cell-mediated autoimmune and inflammatory diseases.

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Extracellular Matrix Lumican Promotes Bacterial Phagocytosis, and Lum−/− Mice Show Increased Pseudomonas aeruginosa Lung Infection Severity

Cited by 43 publications

References 47 publications

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

Lumican negatively controls the pathogenicity of murine encephalitic TH17 cells

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