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CARLOS M. MINUTTI
Tissue-specific signals that modulate IL-4Rα–mediated macrophage activation in lung repair
XIIè CONGRÉS Societat Catalana d’Immunologia (SCI)
16.11.2018
Les macrophages font tout!!!
1884 2018
Élie Metchnikoff
Ruslan Medzhitov
Judi AllenMiriam Merad
Paradigm of macrophage activation
Sources of macrophage diversity: Origin and Niche
from Guilliams & Scott. Nature Reviews Immunology 2017
The alveoli provide an unique niche for macrophages
SP-A is an abundant component of the humoral immune defense in the lungs
SP-A is a member of the family of collectins
adapted from Sanchez-Barbero et al. Biochem. J. 2007
SP-A prevents viral and bacterial infections
adapted from Wright. Nature Immunology 2005
SP-A is also immuno-modulatory
adapted from Wright. Nature Immunology 2005
Does SP-A modulates activation of alveolar macrophages?
?
Mφ(IFN-γ + LPS) Mφ(IL-4)
?
SP-A attenuates classical activation of alveolar macrophages
Minutti et al. The Journal of Immunology 2016
Does SP-A modulates M(IL-4)?
?
Mφ(IFN-γ + LPS) Mφ(IL-4)
Is SP-A a tissue-specific factor?
Alveolar Peritoneal
CD11c+SiglecF+
CD11b+F480+
+ IL-4
?
Does another defense collagen, C1q, modulates IL-4 effects on alveolar and peritoneal Mf?
Alveolar Peritoneal
CD11c+SiglecF+
CD11b+F480+
+ IL-4
??
?
Experimental approach
Platemacrophages
Collagens and/or IL-4
Harvest
1.5 hours 48 hours
Proliferation Alternative activation
∑ BrdU∑ Ki67
∑ RELMα∑ Ym1
BrdU
SP-A and C1q are local tissue-specific amplifiers of IL-4Rα–mediated macrophage activation
Alveolar Mϕ Peritoneal Mϕ
Prol
ifera
tion
Activ
atio
n
Minutti et al. Science 2017
The effects of SP-A and C1q are similar in vivo
A-Mϕ P-Mϕ
Prol
ifera
tion
Activ
atio
n
A-Mϕ P-Mϕ
What is the receptor for SP-A and C1q?
Alveolar Mϕ Peritoneal MϕPr
olife
ratio
nAc
tivat
ion
Where is Myo18A expressed?
What is the effect of C1q in the liver?
Proliferation Activationin
viv
oin
vitr
o
IL-4 also drives local production of SP-A and C1q
LiverLung Peritoneum
What is the physiological relevance of SP-A during a model of type 2 immunity?
Day 6
Chen et al.; Nat Medicine 18,2012
Alveolar macrophages stimulatedwith IL-4/IL-13 are essential tomediate lung repair .
ProliferationAlternative activation
SP-A
?
? ? ?
?
Does SP-A influencethe ability of aMfs to
respond to IL-4?
D0: Subcutaneous inoculation of L3 larvae
D1 D4 D6
Migration
Type 2 macrophage activation decreases and lung damage increases in the absence of SP-A
What is the physiological relevance of C1q in a model of liver damage
from Blériot, et al. Immunity. 2015
WT
C1qa(-/-)
C57BL/6 mice
C1q-deficient mice showed increased liver damage after infection with Listeria monocytogenes
What is the physiological relevance of C1q during a model of peritoneal fibrosis?
from Wang, et al. Int. J. Mol. Sci. 2013
WT
C1qa(-/-)
C57BL/6 mice
Day 0 Day 29Sample
collection
2 4 6 8 10 12 14 16 18 20 22 24 26 28
Dianeal PD-4 administration (i. p.)
Peritoneal dialysis
Peritoneal fibrosis induced by a lactate dialysate is reduced in C1q-deficient mice
Summary
Minutti et al. Science, 2017
Bosurgi et al. Science, 2017
Recognition of apoptotic cells also enhances tissue repair function of macrophages
SP-A increases the phagocytosis of dying cells
adapted from Ravichandran, Journal of Experimental Medicine, 2010
What about the molecular mechanism?
SP-A amplifies IL-4 signaling on alveolar macrophages
P-STAT6 P-Akt
Myosin18A mediates SP-A reinforcement of IL-4-dependent effects
P-STAT6 P-Akt
ModeradorNotas de la presentaciónSTAT6 - Tyr641 Akt - Ser47
Known SP-A’s signaling pathways
PI3KBeharka, et al, JI 2002
P-AktP-PKCζMoulakakis, et al, JI 2007
PI3K inhibitor blocks SP-A effects on p-Akt and p-PKCz
PI3K
P-AktP-PKCζ P-Akt P-PKCζ
ModeradorNotas de la presentaciónPKC - Thr410/403 Akt - Ser47
PI3K inhibitor blocks SP-A actions on IL-4 effects
PI3K
P-AktP-PKCζ
Activation Proliferation
Akt activation controls SP-A and IL-4-mediated macrophage proliferation
PI3K
P-AktP-PKCζ
Activation Proliferation
PKCζ activation mediates SP-A enhancement of IL-4-induced activation of alveolar macrophages
PI3K
P-AktP-PKCζ
Activation Proliferation
Conclusions
IL-4 SP-A
Acknowledgements
Cristina Casals’s lab and CIBERES
Belén García-Fojeda (Mad)Raquel Guillamat-Prats (BCN)Antonio Artigas (BCN)
Judi Allen’s lab
Lucy Jackson-Jones (Ed)Tara Sutherland (Ed)Nicola Logan (Ed)Emma Rinqvist (Ed)
CollaboratorsJohanna Knipper (UK)David Ferenbach (UK) Cordula Stamme (DE)Zissis Chroneos (US)
Dietmar Zaiss’s lab
ES UK
UNIVERSIDAD COMPLUTENSE
Número de diapositiva 1Les macrophages font tout!!!Paradigm of macrophage activationSources of macrophage diversity: Origin and NicheThe alveoli provide an unique niche for macrophagesSP-A is an abundant component of the humoral immune defense in the lungsSP-A is a member of the family of collectinsSP-A prevents viral and bacterial infectionsSP-A is also immuno-modulatoryDoes SP-A modulates activation of alveolar macrophages?SP-A attenuates classical activation of alveolar macrophagesDoes SP-A modulates M(IL-4)?Is SP-A a tissue-specific factor? Número de diapositiva 14SP-A and C1q are local tissue-specific amplifiers of IL-4Rα–mediated macrophage activation The effects of SP-A and C1q are similar in vivoWhat is the receptor for SP-A and C1q?Where is Myo18A expressed?What is the effect of C1q in the liver?IL-4 also drives local production of SP-A and C1qWhat is the physiological relevance of SP-A during a model of type 2 immunity?Type 2 macrophage activation decreases and lung damage increases in the absence of SP-AWhat is the physiological relevance of C1q in a model of liver damageC1q-deficient mice showed increased liver damage after infection with Listeria monocytogenesWhat is the physiological relevance of C1q during a model of peritoneal fibrosis?Peritoneal fibrosis induced by a lactate dialysate is reduced in C1q-deficient miceSummaryNúmero de diapositiva 28SP-A increases the phagocytosis of dying cells What about the molecular mechanism?SP-A amplifies IL-4 signaling on alveolar macrophages Myosin18A mediates SP-A reinforcement of IL-4-dependent effects Known SP-A’s signaling pathwaysPI3K inhibitor blocks SP-A effects on p-Akt and p-PKCPI3K inhibitor blocks SP-A actions on IL-4 effectsAkt activation controls SP-A and IL-4-mediated macrophage proliferationPKCζ activation mediates SP-A enhancement of IL-4-induced activation of alveolar macrophagesConclusionsAcknowledgements