Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma

Pilecki, Bartosz; Schlosser, Anders; Wulf-Johansson, Helle; Trian, Thomas; Møeller, Jesper Bonnet; Marcussen, Niels; Aguilar-Pimentel, Juan Antonio; Angelis, Martin Hrabě de; Vestbo, Jørgen; Berger, Patrick; Holmskov, Uffe; Sørensen, Grith Lykke

doi:10.1136/thoraxjnl-2014-206609

Cited by 43 publications

(46 citation statements)

References 37 publications

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“…We have recently generated MFAP4-deficient mice and shown that they exhibit attenuated airway smooth muscle responses when subjected to an allergic asthma model (64). We have further investigated the steady state phenotype of MFAP4 deficiency and observed that MFAP4-null mice develop a spontaneous loss of lung function with moderate emphysema-like airspace enlargement, which progresses with age (65).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Pilecki

Holm

Schlosser

et al. 2016

Journal of Biological Chemistry

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116

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MFAP4 (microfibrillar-associated protein 4) is an extracellular glycoprotein found in elastic fibers without a clearly defined role in elastic fiber assembly. In the present study, we characterized molecular interactions between MFAP4 and elastic fiber components. We established that MFAP4 primarily assembles into trimeric and hexameric structures of homodimers. Binding analysis revealed that MFAP4 specifically binds tropoelastin and fibrillin-1 and -2, as well as the elastin cross-linking amino acid desmosine, and that it co-localizes with fibrillin-1-positive fibers in vivo. Site-directed mutagenesis disclosed residues Phe 241 and Ser 203 in MFAP4 as being crucial for type I collagen, elastin, and tropoelastin binding. Furthermore, we found that MFAP4 actively promotes tropoelastin self-assembly. In conclusion, our data identify MFAP4 as a new ligand of microfibrils and tropoelastin involved in proper elastic fiber organization.Elastic fibers are key extracellular matrix structural elements of connective tissues that undergo repeated stretch, such as large arteries and the lung (1). The fibers consist of two major components: an amorphous elastin core surrounded by a sheath of fibrillin-rich microfibrils (2). Elastin is a highly hydrophobic polymer of the soluble precursor tropoelastin (3). Tropoelastin is known to undergo a self-assembly process known as coacervation (4), often believed to be a first step in the process of elastic fiber maturation. Because of the high content of lysine residues within the tropoelastin sequence, its assembly into a polymeric form is stabilized by formation of desmosine crosslinks, catalyzed by the lysyl oxidase (LOX) 3 enzyme family (5).Microfibrils, the other major component of elastic fibers, provide the structural scaffold for the deposition of elastin globules. They consist primarily of fibrillin-1 and fibrillin-2, large glycoproteins with a high degree of homology (6). Apart from fibrillins, numerous accessory proteins have been shown to associate with microfibrils or elastin and promote formation of mature fibers, including fibulins and microfibril-associated glycoproteins (MAGPs) (7-10). The importance of proper elastogenesis has been underscored by gene deficiency studies: mice lacking elastin, LOX, or fibrillin-1 die shortly after birth because of vascular abnormalities (11-13).MFAP4 (microfibrillar-associated protein 4) is an extracellular matrix protein belonging to the fibrinogen-related domain (FReD) family. The family includes several proteins engaged in tissue homeostasis and innate immunity, such as FIBCD1 (fibrinogen C domain-containing 1), ficolins, and angiopoietins (14 -16). The crystal structure of the FReD of several family members has been solved (17-19). The ligand-binding site, designated S1, is described in all the proteins and is located in close proximity to the calcium-binding site. MFAP4 has been reported to form homodimeric structures that further oligomerize, but its definite oligomerization pattern has not been established (20).MFAP4 is conside...

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Section: Discussionmentioning

confidence: 99%

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Pilecki

Holm

Schlosser

et al. 2016

Journal of Biological Chemistry

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116

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“…9,10 MFAP4 has recently been shown to promote the development of asthma in vivo and display proasthmatic properties of bronchial smooth muscle cells in vitro and has been suggested to contribute to allergic asthma by promoting airway eosinophilia, airway hyperresponsiveness, and lung remodeling through regulation of ASM proliferation and eotaxin secretion in experimental studies. 11 The objectives of this study were to investigate if the serum level of MFAP4 (sMFAP4) is associated with (a) asthma and (b) allergic sensitization in adolescents and young adults, and (c) whether sMFAP4 at the time of asthma diagnosis is associated with persistent asthma.…”

Section: Introductionmentioning

confidence: 99%

Microfibrillar‐associated protein 4 in serum is associated with asthma in Danish adolescents and young adults

Hoffmann-Petersen

Suffolk

Petersen

et al. 2019

Immunity Inflam & Disease

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Background Microfibrillar‐associated protein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen‐related protein superfamily, which plays multifaceted roles in innate immunity and normal endothelial function. It has been proposed that MFAP4 promotes the development of asthma in vivo and proasthmatic pathways of bronchial smooth muscle cells in vitro. The aim of this study was to investigate the significance of serum MFAP4 in adolescents and young adolescents with persistent asthma. Methods Prospective, observational study including adolescents and young adults (age 11‐27 years) previously diagnosed with asthma during childhood 2003 to 2005 (0‐15 years) at the four pediatric outpatient clinics in the Region of Southern Denmark (n = 449). Healthy controls were recruited at follow‐up (n = 314). Detection of serum MFAP4 was performed by AlphaLISA technique. Results Current asthma was associated to a 14% higher mean level of serum MFAP4 compared with controls (expβ 1.14, 95% confidence intervals [CI], 1.05‐1.23) and a 6% higher mean level compared with subjects with no current asthma (expβ 1.06, 95% CI, 0.99‐1.13). No association was found at follow‐up between serum MFAP4 and self‐reported atopic symptoms (other than asthma), Asthma Control Test‐score, fractional exhaled nitric oxide (FeNO), nor to flow rate at 1 second, forced vital capacity, and forced expiratory flow 25% to 75%, response to short‐acting beta 2 agonist or mannitol. Conclusions We found a significantly higher mean level of serum MFAP4 in adolescent and young adults with mild to moderate asthma compared with healthy controls but no association to FeNO and lung function nor to the response to short‐acting beta 2 agonist or mannitol. The result supports the hypothesis that MFAP4 plays a role in the pathogenesis of asthma although the marker did not demonstrate any obvious potential as an asthma biomarker in adolescents and young adults with asthma. To understand the possible proasthmatic functions of MFAP4, further investigation in specific asthma phenotypes and the underlying molecular mechanisms is warranted.

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“…12,13 MFAP4 has been associated with remodeling-related disorders, including liver fibrosis, 14 pulmonary airspace enlargement, 15 and atherosclerosis. 16 Furthermore, we recently showed that MFAP4 promotes airway SMC proliferation in experimental asthma, 17 suggesting that similar effects could be relevant for VSMC biology under pathological conditions. Moreover, recent in silico analysis predicted that Mfap4 deficiency can result in abnormal vascular physiology.…”

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confidence: 99%

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

Schlosser¹,

Pilecki²,

Hemstra³

et al. 2016

ATVB

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101

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V ascular smooth muscle cell (VSMC) activation and phenotypic switching are critical for remodeling processes in vascular proliferative disorders, including intimal hyperplasia. Both the migratory and proliferative activities of VSMCs, as well as the interplay between the extracellular matrix (ECM) and integrin receptors essentially, contribute to neointimal hyperplasia and restrictive remodeling processes in the vessels.1 Among integrins, the particular role of integrin α V β 3 in the induction of VSMC responses has been shown both in vivo and in vitro.

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Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma

Abstract: MFAP4 promoted the development of asthmatic airway disease in vivo and pro-asthmatic functions of bronchial smooth muscle cells in vitro. Collectively, our results identify MFAP4 as a novel contributor to experimental asthma, acting through modulation of airway smooth muscle cells.

Cited by 43 publications

References 37 publications

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Microfibrillar‐associated protein 4 in serum is associated with asthma in Danish adolescents and young adults

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

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