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Toll-like receptor 7 is reduced in severe asthma and linked to altered microRNA profile

Toll-like receptor 7 is reduced in severe asthma and linked to altered microRNA profile
Toll-like receptor 7 is reduced in severe asthma and linked to altered microRNA profile
RATIONALE:Asthma is one of the commonest chronic diseases worldwide and severe asthma sufferers experience recurrent exacerbations. Exacerbations are predominantly viral-associated and have been linked to defective airway interferon responses. Ascertaining the molecular mechanisms underlying this deficiency is a major research goal in order to identify new therapeutic targets.

OBJECTIVES:We investigated the hypothesis that reduced toll-like receptor (TLR) 7-derived signalling was driving the impaired interferon responses to rhinovirus by asthmatic alveolar macrophages (AMs) and molecular mechanisms underlying this deficiency were explored.

METHODS:AMs were recovered from bronchoalveolar lavage from healthy and severe asthma subjects. Expression of pattern-recognition receptors and microRNAs was evaluated by quantitative PCR and western blotting. A TLR7-luciferase reporter construct was created to evaluate binding of microRNAs to the 3'UTR of TLR7. Interferon production was measured by quantitative PCR and ELISA.

MEASUREMENTS AND MAIN RESULTS:The expression of TLR7 was significantly reduced in severe asthma AMs and was associated with reduced rhinovirus and imiquimod-induced interferon responses by these cells compared to healthy AMs. Severe asthma AMs also expressed increased levels of 3 microRNAs that we showed are able to directly reduce TLR7 expression. Ex vivo knock-down of these microRNAs restored TLR7 expression with concomitant augmentation of virus-induced interferon production.
microrna, TLR, interferon, macrophages, rhinovirus
1073-449X
26-37
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Rupani, Hitasha
cbc7068a-4279-4c8e-b83f-353210711062
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Lau, Laurie
2af8045d-6162-4939-aba7-28dd2f60f6a8
Martinez-Nunez, Rocio Teresa
a6069f08-55cf-4477-b895-9c4fdd2ee5ee
Havelock, Tom
8f9aa3be-a768-4a7b-bcd4-79656e2b188c
Grainge, Chris
a83145e5-cfaf-4dae-a6d8-fb225f460136
Francisco-Garcia, Ana
0d675d21-b92a-4d66-81b6-9f2a82545ade
Jayasekera, Nivenka
2dd458a6-97a3-4c79-b922-2e91c8fc8117
Dennison, Patrick
30c232e3-c218-4dd8-979f-061ac70513d5
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Rupani, Hitasha
cbc7068a-4279-4c8e-b83f-353210711062
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Lau, Laurie
2af8045d-6162-4939-aba7-28dd2f60f6a8
Martinez-Nunez, Rocio Teresa
a6069f08-55cf-4477-b895-9c4fdd2ee5ee
Havelock, Tom
8f9aa3be-a768-4a7b-bcd4-79656e2b188c
Grainge, Chris
a83145e5-cfaf-4dae-a6d8-fb225f460136
Francisco-Garcia, Ana
0d675d21-b92a-4d66-81b6-9f2a82545ade
Jayasekera, Nivenka
2dd458a6-97a3-4c79-b922-2e91c8fc8117
Dennison, Patrick
30c232e3-c218-4dd8-979f-061ac70513d5

Sanchez-Elsner, Tilman, Rupani, Hitasha, Howarth, Peter, Lau, Laurie, Martinez-Nunez, Rocio Teresa, Havelock, Tom, Grainge, Chris, Francisco-Garcia, Ana, Jayasekera, Nivenka and Dennison, Patrick (2016) Toll-like receptor 7 is reduced in severe asthma and linked to altered microRNA profile. American Journal of Respiratory and Critical Care Medicine, 194 (1), 26-37. (doi:10.1164/rccm.201502-0280OC). (PMID:26815632)

Record type: Article

Abstract

RATIONALE:Asthma is one of the commonest chronic diseases worldwide and severe asthma sufferers experience recurrent exacerbations. Exacerbations are predominantly viral-associated and have been linked to defective airway interferon responses. Ascertaining the molecular mechanisms underlying this deficiency is a major research goal in order to identify new therapeutic targets.

OBJECTIVES:We investigated the hypothesis that reduced toll-like receptor (TLR) 7-derived signalling was driving the impaired interferon responses to rhinovirus by asthmatic alveolar macrophages (AMs) and molecular mechanisms underlying this deficiency were explored.

METHODS:AMs were recovered from bronchoalveolar lavage from healthy and severe asthma subjects. Expression of pattern-recognition receptors and microRNAs was evaluated by quantitative PCR and western blotting. A TLR7-luciferase reporter construct was created to evaluate binding of microRNAs to the 3'UTR of TLR7. Interferon production was measured by quantitative PCR and ELISA.

MEASUREMENTS AND MAIN RESULTS:The expression of TLR7 was significantly reduced in severe asthma AMs and was associated with reduced rhinovirus and imiquimod-induced interferon responses by these cells compared to healthy AMs. Severe asthma AMs also expressed increased levels of 3 microRNAs that we showed are able to directly reduce TLR7 expression. Ex vivo knock-down of these microRNAs restored TLR7 expression with concomitant augmentation of virus-induced interferon production.

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Accepted/In Press date: 25 January 2016
e-pub ahead of print date: 27 January 2016
Keywords: microrna, TLR, interferon, macrophages, rhinovirus
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 386771
URI: https://eprints.soton.ac.uk/id/eprint/386771
ISSN: 1073-449X
PURE UUID: 5c147a00-52f8-4c91-a891-8c87a05e1fd7

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Date deposited: 04 Feb 2016 11:29
Last modified: 09 Dec 2019 19:46

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Contributors

Author: Hitasha Rupani
Author: Peter Howarth
Author: Laurie Lau
Author: Rocio Teresa Martinez-Nunez
Author: Tom Havelock
Author: Chris Grainge
Author: Ana Francisco-Garcia
Author: Nivenka Jayasekera
Author: Patrick Dennison

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