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Reduced suppressive effect of ?2-adrenoceptor agonist on fibrocyte function in severe asthma.

ABSTRACT: Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting ?2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of ?2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the ?2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (?-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of ?2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface ?2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased ?2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.

SUBMITTER: Lo CY

PROVIDER: S-EPMC5697384 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Reduced suppressive effect of β<sub>2</sub>-adrenoceptor agonist on fibrocyte function in severe asthma.

Lo Chun-Yu CY Michaeloudes Charalambos C Bhavsar Pankaj K PK Huang Chien-Da CD Chang Po-Jui PJ Wang Chun-Hua CH Kuo Han-Pin HP Chung Kian Fan KF

Respiratory research 20171121 1

<h4>Background</h4>Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β<sub>2</sub>-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β<sub>2</sub>-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.<h4>Methods</h4>Non-adherent non-T cells from peripheral blood ...[more]

PMID: 29162108

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Project description:The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR-the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR-βarr1 complex than for the β1AR-Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors.

Dataset Information

Reduced suppressive effect of ?2-adrenoceptor agonist on fibrocyte function in severe asthma.

Publications

Reduced suppressive effect of β<sub>2</sub>-adrenoceptor agonist on fibrocyte function in severe asthma.

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