Implication de la voie IL-17 / IL-22 dans la susceptibilité aux infections associée à la broncho-pneumopathie chronique obstructive (BPCO)

Abstract : Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways mainly due to chronic exposure to cigarette smoke. Evolution of the disease is often associated with bacterial colonization of the airways and punctuated by acute exacerbation of the disease with a frequent related morbi-mortality. These exacerbations are mainly due to infection and almost 50 % are associated with bacteria, often Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Th17 immune response is particularly involved in control of bacterial infection and is principally mediated by IL-17A and IL-22 cytokines. This Th17 inflammation is involved in COPD physiopathology but there is paucity of data focusing on this immune response during COPD exacerbations. Our hypothesis is that Th17 immune response to pathogens is defective in COPD leading to airways infection susceptibility.We have tested our hypothesis by different approaches. First, the ex vivo responses to Streptococcus pneumoniae of peripheral blood mononuclear cells (PBMC) from COPD patients, healthy non smokers and healthy smokers were compared showing decreased production of IL-17A and IL-22 but also of pro-Th17 cytokines IL-6 and IL-23 which are produced by antigen presenting cells (APC). Second, we used an in vitro model of monocyte-derived dendritic cells (MDDC) exposed to cigarette smoke showing a defective MDDC maturation, pro-Th17 cytokines production and ability to promote T-cells Th17 response, in response to S. pneumoniae. Finally, an in vivo murine model of mice chronically exposed to cigarette smoke showing defective production of IL-17A and IL-22 but also of pro-Th17 cytokines IL-1β and IL-23 produced by APC, in response to S. pneumoniae. In this model, supplementation with IL-22 restored bacterial clearance and limited lung alterations suggesting therapeutic opportunities to improve infectious COPD exacerbation management.Altogether, these results strengthen our hypothesis of a defective Th17 immune response during bacterial COPD exacerbations. They are comforted by other studies in our team showing a defective IL-22 production in response to Haemophilus influenzae in our in vivo model of mice chronically exposed to cigarette smoke. Now we have to confirm these results in a clinical trial including COPD patients in exacerbation and to further explore the impact on innate lymphoid cells, which produced these cytokines, and on the innate immune response of epithelial cells to infection, in order to develop new infectious COPD exacerbation therapeutics.
Document type :
Theses
Complete list of metadatas

https://tel.archives-ouvertes.fr/tel-01891091
Contributor : Abes Star <>
Submitted on : Tuesday, October 9, 2018 - 11:35:50 AM
Last modification on : Monday, March 4, 2019 - 3:40:04 PM
Long-term archiving on : Thursday, January 10, 2019 - 1:53:39 PM

File

2016LIL2S020.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-01891091, version 1

Collections

Citation

Olivier Le Rouzic. Implication de la voie IL-17 / IL-22 dans la susceptibilité aux infections associée à la broncho-pneumopathie chronique obstructive (BPCO). Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2016. Français. ⟨NNT : 2016LIL2S020⟩. ⟨tel-01891091⟩

Share

Metrics

Record views

70

Files downloads

20