Laisse parler ton cœur, interroge les visages, n'écoute pas les langues... Umberto Eco

Laisse parler ton cœur, interroge les visages, n'écoute pas les langues...

Umberto Eco

REMERCIEMENTS

Je tiens tout d’abord à saluer chaleureusement mon promoteur, le Professeur Fabrice Bureau, sans qui ce travail n’aurait jamais pu aboutir. Sa disponibilité, sa générosité, ses nombreux encouragements et ses précieux conseils ont été autant d’atouts indispensables pour m’aider à franchir les différents obstacles de la réalisation d’une thèse de doctorat. Son exemple influencera sans aucun doute mes choix futurs positivement et je lui en suis particulièrement reconnaissant.

Je tiens aussi à exprimer ma profonde gratitude à mon co-promoteur, le Professeur Pierre Lekeux, pour m’avoir attiré vers la recherche et ensuite laissé la liberté d’orienter ma thèse de doctorat comme je le souhaitais. Je suis sûr que ses nombreux conseils me seront très longtemps utiles et je le remercie sincèrement pour son soutien indéfectible.

Un énorme merci à Hugues Wallemacq, véritable « Grichka » du laboratoire, pour son aide lors de la mise au point des différentes techniques mais surtout pour tous les excellents moments passés ensemble et sa précieuse amitié !

Je remercie sincèrement Christophe Desmet et Thomas Marichal dont l’aide dans la dernière ligne droite a été redoutablement efficace.

Merci à tous les membres, anciens ou plus jeunes, de l’équipe de Physiologie Cellulaire et Moléculaire : Agnieszka Legutko, Barbara Warzée, Claire Mesnil, Laurence Fiévez, Marie Toussaint, Sabine Olivier, Cédric François, Dimitri Pirottin et Philippe Boutet, pour l’excellente ambiance du service et pour toute leur aide pendant ces années passées ensemble.

Merci à Ilham Sbaï pour son excellente assistance administrative, au Professeur Tania Art pour avoir encadré mes premiers pas et à toute l’équipe de Physiologie pour leur bonne humeur.

Je ne peux terminer ce passage sans une pensée pour notre collègue et surtout ami Rodrigue Closset qui nous a quittés beaucoup trop tôt et dont le souvenir ne cessera de m’accompagner...

Mes remerciements vont au Professeur Didier Cataldo pour m’avoir ouvert les portes de son laboratoire et à Florence Quesada Calvo pour m’avoir aidé à réaliser de nombreuses manipulations telles que la mesure de l’hyperréactivité bronchique et le dosage des immunoglobulines sériques spécifiques de l’ovalbumine.

Merci beaucoup au Professeur Muriel Moser, à Marjorie Vermeersch et à Bernard Pajak pour leurs précieux conseils et leur aide technique qui nous ont permis de résoudre les problèmes que nous posait la réalisation des marquages immunohistologiques du poumon.

Merci au Professeur Pierre-Vincent Drion pour nous avoir permis de travailler dans de bonnes conditions sur nos modèles animaux après notre déménagement au GIGA.

Le Professeur Alain Vanderplasschen m’a laissé pénétrer dans son laboratoire où j’ai ainsi pu, grâce à Benjamin Dewals, me former à la cytométrie en flux, technique qui s’est révélée être particulièrement importante pour la réalisation de cette étude.

Merci à Nathalie Guillaume pour avoir relu ma thèse et m’avoir aidé à la déposer dans les délais.

Ce travail n’aurait pu être réalisé sans le soutien financier du Fonds National de la Recherche Scientifique. Je remercie également la société GlaxoSmithKline Biologicals pour avoir soutenu mes deux premières années de mandat d’aspirant du FNRS.

Je remercie le Professeur Hélène Amory pour avoir accepté de faire partie de mon comité de thèse ainsi que les Professeurs et Docteurs Carole Charlier, Muriel Pichavant, Nadine Antoine, Bernard Mignon, Dominique Peeters, Jean-Christophe Renauld et Laurent Gillet pour avoir accepté d’évaluer mon travail.

Je tiens également à remercier le président du Collège de Doctorat, le Professeur Daniel Desmecht pour m’avoir patiemment expliqué les différentes étapes de la nouvelle mouture de l’épreuve de doctorat et les Professeurs Michel Georges et Renaud Louis pour m’avoir aidé à décrocher une bourse de post-doctorat.

Un merci particulier au Professeur Pascal Leroy pour les conseils et l’aide qu’il me prodigue depuis le début de mes études.

Je n’aurais certainement pas pu mener à bien ce travail sans le soutien de mes proches, mes amis,

ma famille et particulièrement mes parents qui ont toujours soutenu mes choix. Enfin, je profite de

l’occasion pour exprimer toute ma gratitude à Sandy qui a eu le « privilège » de me supporter

depuis le début de cette thèse. Je la remercie pour sa patience, son soutien, son aide efficace et pour

m’avoir, avec l’aide de notre adorable Lisa, rappelé, sans chercher à m’en détourner, qu’il existait

autre chose dans la vie que la recherche.

TABLE DES MATIERES

LISTE DES ABREVIATIONS 5

RESUME 8

SUMMARY 9

INTRODUCTION 10

I. A

STHME

10

I.1. Généralités 10

I.2. Epidémiologie 10

I.3. Signes cliniques de l’asthme 11

I.4. Physiopathologie de la réaction asthmatique 11

I.4.1. I

NFLAMMATION

11

I.4.2. R

EMODELAGE DES VOIES AERIENNES

12

I.4.2.1. Généralités 12

I.4.2.2. Hypersécrétion de mucus 14

I.4.3. B

RONCHOCONSTRICTION

15

I.4.4. H

YPERREACTIVITE BRONCHIQUE NON SPECIFIQUE

15

I.4.4.1. Hyperréactivité variable (ou inductible) 16

I.4.4.2. Hyperréactivité persistante 16

I.5. Asthme et Médecine vétérinaire 17

II. M

ÉCANISMES CELLULAIRES IMPLIQUÉS DANS L

’

ASTHME

18

II.1. Les mastocytes 19

II.2. Les granulocytes 22

II.2.1. L

ES BASOPHILES

22

II.2.2. L

ES EOSINOPHILES

23

II.2.3. L

ES NEUTROPHILES

24

II.3. Les lymphocytes B 25

II.4. Les lymphocytes T 27

II.4.1. L

ES LYMPHOCYTES

T

HELPER DE TYPE

2 27

II.4.2. L

ES LYMPHOCYTES

T

HELPER DE TYPE

17 29

II.4.3. L

ES LYMPHOCYTES

T

REGULATEURS

30

II.4.4. L

ES LYMPHOCYTES

T N

ATURAL

K

ILLER

32

II.5. Les cellules dendritiques 34

II.6. Les macrophages 37

II.7. Les cellules épithéliales 38

III. R

ÔLE DES MACROPHAGES DANS L

’

ASTHME

39

III.1. Généralités sur les macrophages 39

III.2. Caractérisation phénotypique des macrophages 42

III.3. Classification des macrophages 43

III.3.1. M

ACROPHAGES CLASSIQUEMENT ACTIVES VS ALTERNATIVEMENT ACTIVES

43

III.3.2. C

LASSIFICATION BASEE SUR LA FONCTION DES MACROPHAGES

43

III.4. Macrophages pulmonaires 45

III.4.1. M

ACROPHAGES ALVEOLAIRES

46

III.4.2. M

ACROPHAGES INTERSTITIELS

46

IV. A

STHME ET ENVIRONNEMENT

48

IV.1. Généralités 48

IV.2. Cas particulier des endotoxines 50

IV.2.1. S

OURCES

50

IV.2.2. S

TRUCTURE

50

IV.2.3. V

OIES DE SIGNALISATION

51

IV.2.3.1. Activation du TLR4 51

IV.2.3.2. Voies de signalisation induites par l’activation du TLR4 52

IV.2.4. E

NDOTOXINES ET ASTHME

53

IV.2.4.1. Les endotoxines comme facteur protecteur de l’asthme 53 IV.2.4.2. Les endotoxines comme facteur aggravant de l’asthme 54

IV.2.5. C

ONCLUSION

56

OBJECTIF DU TRAVAIL 57

RESULTATS 58

I. C

ARACTÉRISATION DES MACROPHAGES INTERSTITIELS

58

II. L

ES MACROPHAGES INTERSTITIELS

,

MAIS PAS LES MACROPHAGES ALVÉOLAIRES

,

SONT CAPABLES DE PRÉVENIR L

’

ALLERGIE DES VOIES RESPIRATOIRES INDUITE PAR DES CELLULES DENDRITIQUES PULSÉES À L

’

OVALBUMINE

(OVA)

ET STIMULÉES AU

LPS 62 III. L

ES MACROPHAGES INTERSTITIELS SONT CAPABLES D

’

INHIBER L

’

ACTIVATION PRIMAIRE DES LYMPHOCYTES

T

DÉCLENCHÉE PAR DES CELLULES DENDRITIQUES PULSÉES À L

’OVALPS 68 IV. L

ES MACROPHAGES INTERSTITIELS SONT CAPABLES D

’

AFFECTER LA MATURATION ET LA MIGRATION DES CELLULES DENDRITIQUES ACTIVÉES PAR LE

LPS 70 V. L

ES MACROPHAGES INTERSTITIELS EXERCENT LEURS EFFETS INHIBITEURS VIA LA

PRODUCTION D

’IL-10 74

VI. L

ES MACROPHAGES INTERSTITIELS PRÉVIENNENT LES RÉPONSES

T

H

2

AUX ANTIGÈNES

INOFFENSIFS INHALÉS CONCOMITAMMENT À DU

LPS 78

VII. L

ES EFFETS SUPPRESSEURS DES MACROPHAGES INTERSTITIELS NE DÉPENDENT PAS DE

L

’

INDUCTION D

’

UNE TOLÉRANCE IMMUNOLOGIQUE

83

DISCUSSION 85

CONCLUSION ET PERSPECTIVES 91

MATERIEL ET METHODES 94

BIBLIOGRAPHIE 103

LISTE DES ABRÉVIATIONS

ABC : Avidin-biotin-complex AM : Macrophage alvéolaire AMP : Adénosine monophosphate AP-1 : Activator protein 1

APC : Allophycocyanin

BAL(F) : (Liquide de) lavage bronchoalvéolaire BMDC : Bone marrow-dendritic cell

BSA : Bovine serum albumin

CFSE : Carboxyfluorescein diacetate succinimidyl ester CTLA : Cytotoxic T-lymphocyte antigen

CX

3

CR1 : CX

3

-chemokine receptor 1 DAPI : 4',6' diamidino-2-phényl indole DC : Cellule dendritique

ECP : Eosinophil cationic protein EGFR : Epidermal growth factor receptor FcεRI : Récepteur de haute affinité des IgE FCS : Sérum fœtal bovin

FITC : Fluorescein isothiocyanate FoxP3 : Forkhead box P3

GITR : Glucocorticoid-induced tumor necrosis factor receptor GM-CSF : Granulocyte-macrophage colony-stimulating factor GPCR : G-protein-coupled receptor

HRP : Horseradish peroxidase ICOS : Inducible T-cell co-stimulator IDO : Indolémaine 2,3 dioxygénase IFN : Interféron

IκB : Inhibitor of κ light chain enhancer in B cells IgE : Immunoglobuline de type E

IL : Interleukine

IM : Macrophage interstitiel

iNKT : NKT de type I ou invariant

i.t. : intratrachéal i.v. : intraveineux

LPB : LPS binding-protein LPS : Lipopolysaccharide LT : Leucotriènes

M1 : Macrophages classiquement activés

M2 : Macrophages alternativement activés (ou AAMs) MACS : Magnetic cell sorting

MD2 : Myeloid differentiation protein 2 MHC : Major histocompatibility complex MIP : Macrophage inflammatory protein

MyD88 : Myeloid differentiation primary response gene 88 NKT : Natural killer T

OVA : Ovalbumine

PAMP : Pathogen-associated molecular pattern PAS : Periodic acid Schiff

PBS : Phosphate buffer saline PDL : Programmed death ligand PE : Phycoerythrin

Penh : Enhanced pause

PI3K : Phosphatidylinositol 3-kinase PLSD : Protected least standard deviation PLZF : Promyelocytic leukemia zinc finger RIP1 : Receptor interacting protein 1 RSV : Respiratory syncytial virus SCF : stem cell factor

DS : Déviation standard

sRaw : Résistance spécifique des voies respiratoires STAT : signal transducer and activator of transcription Th : T helper

TCM : Tissue culture medium TCR : T cell receptor

TGF : Transforming growth factor

TIR : Toll/Interleukin-1 receptor

TLR : Toll-like receptor

TNF : Tumor necrosis factor

TSLP : Thymic stromal lymphopoietin

VCAM : vascular- cell adhesion molecule

VLA : Very late antigen

RÉSUMÉ

Le système respiratoire est continuellement exposé à de nombreux antigènes environnementaux non pathogéniques. En l’absence de signal proinflammatoire, l’inhalation d’antigènes inoffensifs aboutit au développement d’une tolérance immunologique. Dans ces conditions, les cellules dendritiques pulmonaires tolérogènes stimulent le développement de lymphocytes T régulateurs. Cependant, les études épidémiologiques montrent que l’air ambiant ne contient pas que des antigènes inertes mais également des molécules immunostimulatrices d’origine microbienne dont les endotoxines (LPS, lipopolysaccharide). La présence dans l’environnement de ce composant de la paroi des bactéries Gram négatives est ubiquiste. Malgré le fait que l’exposition à de hauts niveaux de LPS durant l’enfance semble protéger contre la sensibilisation allergique, la plupart des études montrent que les endotoxines contenues dans la poussière domestique constituent un facteur de risque significatif pour la prévalence et la sévérité de l’asthme. Quand le système respiratoire est stimulé par le LPS aérogène, les cellules dendritiques perdent leurs propriétés tolérogènes et deviennent capables d’induire le développement d’une réponse allergique. Bien que les endotoxines soient omniprésentes dans l’environnement et favorisent l’allergie des voies respiratoires, seulement une minorité de personnes est asthmatique. Ces observations contradictoires impliquent l’existence de mécanismes protecteurs non encore décrits capables de prévenir les réponses allergiques induites par les endotoxines. Nous montrons dans ce travail que l’allergie des voies respiratoires induite par le LPS est étroitement contrôlée par les macrophages interstitiels, une sous-population de macrophages pulmonaires dont la fonction in vivo n’avait jamais été caractérisée. Les macrophages interstitiels peuvent être distingués des macrophages alvéolaires par leur capacité unique à inhiber la maturation et la migration des cellules dendritiques induites par l’exposition du système respiratoire au LPS, prévenant ainsi la sensibilisation aux aéroantigènes inhalés concomitamment.

De plus, nous démontrons que l’inhibition fonctionnelle des cellules dendritiques implique la

sécrétion d’IL-10 par les macrophages interstitiels. Finalement, nous montrons que l’élimination

spécifique des macrophages interstitiels in vivo aboutit au développement d’une réponse

asthmatique dirigée contre les aéroantigènes inoffensifs inhalés avec de faibles doses de LPS. Notre

travail révèle un rôle crucial des macrophages interstitiels dans le maintien de l’homéostasie

immunitaire du tractus respiratoire et fournit une explication au paradoxe que le LPS aérogène a la

capacité de favoriser l’induction de réponses Th2 par les cellules dendritiques mais ne provoque pas

d’allergie des voies respiratoires dans les conditions normales. En présence de LPS, les

macrophages interstitiels, mais pas les macrophages alvéolaires, brisent le lien entre l’immunité

innée et l’immunité adaptative, permettant aux antigènes inhalés d’échapper aux réponses

dépendantes des lymphocytes T.

SUMMARY

Respiratory mucosal surfaces are constantly exposed to a broad range of non-pathogenic environmental antigens. In the absence of proinflammatory signals, inhalation of harmless antigens results in immunological tolerance. Indeed, lung dendritic cells stimulate the development of antigen-specific regulatory T cells. Nevertheless, epidemiological studies have shown that ambient air contains not only inert antigens but also immunostimulatory molecules of microbial origin. Of particular interest are endotoxins, a cell wall component of gram-negative bacteria that is ubiquitous in the environment. In spite of the fact that high levels of endotoxin exposure in early life protect against allergic sensitization, most evidence indicates that exposure to house-dust endotoxin is a significant risk factor for increased asthma prevalence and severity. When the respiratory tract is stimulated with airborne endotoxins, lung dendritic cells lose their tolerogenic properties and rather promote the development of an allergic response directed against concomitant aeroantigens.

Although endotoxins are omnipresent in the environment and favour airway allergy, only a minority

of people develops asthma. A unifying model reconciling these conflicting observations is still

lacking. We report here that LPS-triggered airway allergy is tightly controlled by lung interstitial

macrophages, a cell population that remains largely uncharacterized. Interstitial macrophages could

be distinguished from alveolar macrophages by their unique capacity to inhibit lung dendritic cell

maturation and migration upon LPS stimulation, thereby preventing sensitization to concomitant

inhaled antigens. We furthermore demonstrated that functional paralysis of LPS-stimulated

dendritic cells involves interleukin-10 production by interstitial macrophages. Finally, we

demonstrate that specific in vivo elimination of interstitial macrophages leads to overt asthmatic

reactions to innocuous airborne antigens inhaled along with low LPS doses. Our study thus reveals

a crucial role for interstitial macrophages in maintaining immune homeostasis in the respiratory

tract and provides an explanation for the paradox that airborne LPS has the ability to promote the

induction of Th2 responses by lung dendritic cells but does not provoke airway allergy under

normal conditions. In the presence of LPS, interstitial macrophages, but not alveolar macrophages,

break the link between innate and adaptive immunity, allowing harmless inhaled antigens to escape

from T cell-dependent responses.

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