Fibroblasts secrete Slit2 to inhibit fibrocyte differentiation and fibrosis

Pilling, Darrell; Zheng, Z; Vakil, Varsha; Gomer, Richard H.

doi:10.1073/pnas.1417426112

Cited by 78 publications

(78 citation statements)

References 62 publications

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“…Human blood was obtained with written consent and with specific approval from the Texas A&M University human subjects Institutional Review Board. Human PBMC, monocytes, and fibroblasts were isolated, cultured, and incubated with antibodies, as described (37,41). Fibrocytes were identified as described (13,37).…”

Section: Methodsmentioning

confidence: 99%

“…Fibrocytes were identified as described (13,37). Fibroblast conditioned medium was fractionated, and the immunodepletion of lumican was performed, as described (13,41). Pulmonary fibrosis in mice was induced by bleomycin instillation, as described previously (52,72,73).…”

Section: Methodsmentioning

confidence: 99%

“…Using mass spectrometry of tryptic digests from fraction 25, we identified several components of the active peak (Table S1). Of these, only albumin, the proteoglycan lumican, and the neuronal factor Slit2 are known to be extracellular proteins (40,41). We previously observed that albumin does not regulate fibrocyte differentiation (37), and that Slit2 inhibits fibrocyte differentiation (41), suggesting that lumican may be the fibrocyte-inducing factor in FCM+TNF-α.…”

Section: Significancementioning

confidence: 99%

“…Of these, only albumin, the proteoglycan lumican, and the neuronal factor Slit2 are known to be extracellular proteins (40,41). We previously observed that albumin does not regulate fibrocyte differentiation (37), and that Slit2 inhibits fibrocyte differentiation (41), suggesting that lumican may be the fibrocyte-inducing factor in FCM+TNF-α. To determine whether TNF-α increased lumican levels in human lung fibroblasts, cells were incubated in the presence or absence of TNF-α for 2 d. Compared with cells cultured in the absence of TNF-α, cells cultured in the presence of TNF-α had increased lumican staining and increased lumican levels in the conditioned medium (Fig.…”

Section: Significancementioning

confidence: 99%

“…We previously found that fibroblasts secrete the neuronal guidance protein Slit2, and that Slit2 inhibits fibrocyte differentiation (41). To determine how lumican and Slit2 might compete to regulate fibrocyte differentiation, PBMC were cultured in SFM in the absence or presence of 10 μg/mL lumican and 500 pg/mL Slit2.…”

Section: Sap Competes With Lumican To Regulate Fibrocyte Differentiatmentioning

confidence: 99%

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

Pilling

Vakil

Cox

et al. 2015

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

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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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Sap Competes With Lumican To Regulate Fibrocyte Differentiatmentioning

confidence: 99%

See 3 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.

Self Cite

114

103

View full text Add to dashboard Cite

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Role of the Neutrophil Chemorepellent Soluble Dipeptidyl Peptidase IV in Decreasing Inflammation in a Murine Model of Arthritis

Herlihy

Brown

Pilling

et al. 2015

Arthritis & Rheumatology

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Objective To determine whether an intraarticular injection of the neutrophil chemorepellent dipeptidyl peptidase IV (DPPIV; CD26) can attenuate inflammation and decrease the severity of arthritis in a murine model. Methods DBA/1 mice were immunized with type II collagen/Freund's complete adjuvant to produce collagen-induced arthritis (CIA). On day 25 postimmunization, recombinant human DPPIV (rhDPPIV) or phosphate buffered saline was injected intraarticularly, and arthritis severity scores were recorded 3 times per week. The hind legs of mice in both groups were fixed, decalcified, paraffin embedded, and sectioned. Pathologic scores for inflammation and neutrophil infiltration were recorded on a scale of 1–8, and the number of neutrophils was determined by morphometric cell counts. In addition, Mac-2–positive macrophages and articular damage were assessed using anti–Mac-2 antibodies and histologic staining, respectively. Results Injection of rhDPPIV reduced the mean score of arthritis severity in mice with CIA. DPPIV treatment reduced the overall extent of inflammation and articular damage around the arthritic joint and periarticular tissue, and also decreased neutrophil and macrophage infiltration. Conclusion A localized injection of the neutrophil chemorepellent DPPIV reduces inflammation and the severity of the disease in a murine model of arthritis.

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Netrin‐1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin‐Induced Pulmonary Fibrosis

Sun

Zhu

Pan

et al. 2016

Arthritis & Rheumatology

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Objectives Fibrocytes are collagen-producing leukocytes that accumulate in Scleroderma-associated interstitial lung disease (SSc-ILD) via unknown mechanisms. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in Scleroderma has not been explored. This study uses a novel translational platform based on decellularized human lungs to determine whether the scleroderma lung ECM controls fibrocyte development from peripheral blood mononuclear cells. Methods Decellularized scaffolds prepared from healthy and fibrotic Scleroderma lung explants underwent biomechanical evaluation using tensile testing and biochemical analysis using proteomics. Cells from healthy and SSc-ILD subjects were cultured on these scaffolds, and CD45+Pro-ColIα1+ cells meeting criteria for fibrocytes were quantified. The contribution of Netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and via the inhalational administration of bleomycin to Netrin-1+/− mice. Results Compared to control lung scaffold, SSc-ILD lung scaffolds showed aberrant anatomy, enhanced stiffness, and abnormal extracellular matrix composition. Culture of control cells in Scleroderma scaffolds increased Pro-ColIα1+ production, which was stimulated by enhanced stiffness and abnormal ECM composition. SSc-ILD cells demonstrated increased Pro-ColIα1 responsiveness to Scleroderma lung scaffolds, but not enhanced stiffness. Enhanced Netrin-1 expression was seen on CD14lo SSc-ILD cells and antibody mediated Netrin-1 neutralization attenuated CD45+Pro-ColIα1+ detection in all settings. Netrin-1+/− mice were protected from bleomycin induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in Scleroderma lung matrices regulate fibrocyte accumulation via a Netrin-1-dependent pathway. Netrin-1 regulates bleomycin induced murine pulmonary fibrosis. Netrin-1 might be a novel therapeutic target in SSc-ILD.

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Fibroblasts secrete Slit2 to inhibit fibrocyte differentiation and fibrosis

Cited by 78 publications

References 62 publications

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

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

Role of the Neutrophil Chemorepellent Soluble Dipeptidyl Peptidase IV in Decreasing Inflammation in a Murine Model of Arthritis

Netrin‐1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin‐Induced Pulmonary Fibrosis

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