1
Director, Lydia Becker Institute ofImmunology and Inflammation
University of Manchester, [email protected]
Decision making in lung immunity
Professor Tracy [email protected]
• Tissue complexity• Homeostasis• Normal processes that do not stop
Multiple factors affecting macrophage inflammatory tone
9.4
1.4
0.7
0.1
ApoeF13a1H2-EaCd63Prkcb1H2-Ab1CkbMfge8AA467197H2-DMb1Fcgr2bEcm1LOC641240Serpina3gSlc6a8Ppap2bCcr5Lat2Lyz1S100a6AnpepNav1Cd74Iap
Nusap1Igf2bp2Ppap2aTk1AsnsLrig32310046K01RikP2ry13Wfdc10Acot1Prc1Trem1RhofCidecMyo6LipfWtipTnfaip8Nrn1Vstm2aAcaa1bKrt79Nt5eCar4
0 400 3000
No difference in 6526 probes
Hig
her
expr
essi
on ib
res
olve
dAM
PLo
wer
exp
ress
ion
in r
esol
vedA
MP
NiaveAMP ResolvedAMP
No difference in 43 miRNAs
let-7b1851521629c42522129b27a378
9324324-5p484328125a-5p200b450-5p322503
0 1 3
11
Fol
d ch
ange
0.2
0.8
1
A B
Fol
d ch
ange
Ch 15:
Ch X:70bp
50401332 50407161 50407432
5740bp 201bp
C
Fold change
Fluorescence intensity
D
E
85537033
622bp
85537749
99bp 94bp
let-7c294bp 84bp
-3
-2
-1
0
Naive
Res
olve
d
∆∆C
T
-6
-4
-2
0
Nai
veR
esol
ved
∆∆
CT
ResolvedAMPNiaveAMP
let-7b
450a
9.4
1.4
0.7
0.1
ApoeF13a1H2-EaCd63Prkcb1H2-Ab1CkbMfge8AA467197H2-DMb1Fcgr2bEcm1LOC641240Serpina3gSlc6a8Ppap2bCcr5Lat2Lyz1S100a6AnpepNav1Cd74Iap
Nusap1Igf2bp2Ppap2aTk1AsnsLrig32310046K01RikP2ry13Wfdc10Acot1Prc1Trem1RhofCidecMyo6LipfWtipTnfaip8Nrn1Vstm2aAcaa1bKrt79Nt5eCar4
0 400 3000
No difference in 6526 probes
Hig
her
exp
ress
ion
ib r
esol
vedA
MP
Low
er e
xpre
ssio
n in
re
solv
edAM
P
NiaveAMP ResolvedAMP
No difference in 43 miRNAs
let-7b1851521629c42522129b27a378
9324324-5p484328125a-5p200b450-5p322503
0 1 3
11
Fol
d ch
ange
0.2
0.8
1
A B
Fol
d ch
ange
Ch 15:
Ch X:70bp
50401332 50407161 50407432
5740bp 201bp
C
Fold change
Fluorescence intensity
D
E
85537033
622bp
85537749
99bp 94bp
let-7c294bp 84bp
-3
-2
-1
0
Naive
Res
olve
d
∆∆C
T
-6
-4
-2
0
Nai
veR
esol
ved
∆∆
CT
ResolvedAMPNiaveAMP
let-7b
450a
Naive Resolved
Blind folding airway macrophages: miRNA modifications
Dr Alexander Godlee
The impact of the extracellular matrix on inflammation. Lydia SorokinNature Reviews Immunology volume 10, pages 712–723 (2010)000
collagen type XVIII alpha 1 chain Nephronectin: binds
integrin a8b1
The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung diseaseGerald Burgstaller, Bettina Oehrle, Michael Gerckens, Eric S. White, Herbert B. Schiller, Oliver Eickelberg. European Respiratory Journal 2017, 50: 1601805; DOI: 10.1183/13993003.01805-2016
Fibrillar collagen Fibronectin
X-linked fibrillar
collagen
Basal membrane Hyaluronan
Myofibroblast Tenascin C IntegrinsFibroblast
Hyaluronan is a major constituent of the inflamed lung
Why does matrix persist? Production versus degradation
Digestion of HA restores lung function
Hyaluronidase at d15 after influenza
Mechanosensing podosomes exert a protrusive force that senses environment stiffness
F-actin-rich cone-shaped structures ~600 nm height and submicron diameter,
Located at the basal face of cells, perpendicular to, and in contact with, the substratum via integrins at the podosome ring
Typical lifespan of 10 min, with an actin turnover of ~30 s
Fujimori T, Grabiec AM, Kaur M, Bell TJ, Fujino N, Cook PC, Svedberg FR, MacDonald AS, Maciewicz RA, Singh D, Hussell T. Mucosal Immunol. 2015;8(5):1021-30.
Cell death: A double edged sword in lung repair
monoMDMAMΦ
CD36BAI1
TIM1TIM3
TIM4 AxlMerTK
Tyro3
0
25
50
250
500
rela
tive
mR
NA
exp
ress
ion MDM
Actin
Axl
MerTK
AMΦ
Differential expression of TAM receptors on human macrophage subsets
Grabiec AM, Denny N, Doherty JA, ……Fowler SJ, Simpson A, Hussell T.Diminished airway macrophage expression of the Axl receptor tyrosine kinase is associated with defective efferocytosis in asthma.J Allergy Clin Immunol. 2017 Apr 12. (17)30585-7.
Cell death: A double edged sword in lung repair
HD asthma0.0
0.5
1.0
1.5**
extr
acel
lula
r nu
cleo
som
e [A
405]
AMΦ
HD asthma101
102
103
104
***
sputum
HD asthma10-2
10-1
100
101**
rela
tive
sAxl
leve
ls [
a.u.
]
Apoptotic sensing by lung basal cells
Multitasking basal cells: combining stem cell and innate immune duties.Shaykhiev R. Eur Respir J. 2015 Oct;46(4):894-7
P63 Survivin DAPI
Sym
met
ricAsy
mm
etric
P63 Survivin
8 days post influenza infection
Basal cells respond to local cues:
apoptotic cells
AXL drives basal cell proliferation
Rock JR, Randell SH, Hogan BL. Dis Model Mech. 2010 Sep-Oct;3(9-10):545-56. Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodelling.
Basal cell hyperplasia
Epithelial macrophage cross-talk via the Glial cell line-derived neurotrophic factor family
Key roles in the control of neuron survival and differentiation.
Distant members of the TGF-β superfamily
Neurturin influences inflammatory responses and airway remodeling in different mouse asthma models.Mauffray M, Domingues O, Hentges F, Zimmer J, Hanau D, Michel T. J Immunol. 2015;194(4):1423-33.
Neuturin and its receptor in the lung
Emma Connolly
Human Bronchial epithelial cells (Beas-2b)
Not all cells are affected equally
Dr Sylvia Liu
Most variable genes that define these clusters
Bind CXCR2Recruits Mono and neuts
IFN-response geneInduces apoptosisIn same group as IFITM3/M2
Where are the opportunities?
Health at different life stagesWhat drives change?
Infants
(n=20)
Adults
(n=20)
Age, median(range) 11 months (6-23) 59 years (36-78)
BAL fluid instilled (mL), median 15 (5-20) 50 (40-100)
BAL fluid retrieval (%), median 20 (5-40) 40 (20-66)
AM yield (cells x 105), median 2.9 (1.8-18) 2.35 (1.2-13)
Do the same pathways explain immune deficits in infants?
Matched for sex and ethnicityAll healthy diagnosis
Dr Anu GoenkaProf Peter Arkwright
Restoring tissue physiology to limit “inflammatory” disease
Inflamed tissues or trapped inflammatory cells?
Do our lungs become more stromal as we age
Is there a good and bad placental environment – training pre-birth.
Thanks to:Lab members: Dr Sylvia LiuDr Dave MorganDr Emma ConnollyDr Anu GoenkaDr Ben MulhearnDr Chris JaggerJakub ChudziakDr Christine ChewDr Oliver BlandMirium FranklinSarah Warbach
Past members:
Dr Alek GrabiecDr Naoya FujinoDr Toshifumi FujimoriDr Tom BellDr Manminder KaurDr Samira Salek-ArdakaniDr Mark FifeDr Lauren Cholewa
Dr Maryam HabibzayDr Alexandra Godlee Dr John Goulding Dr Robert SandersDr Robert Snelgrove
Clinical colleagues:Professor Angela SimpsonProfessor Stephen FowlerProfessor Rob NivenProfessor Jurgen Vestbo