Decision making in lung immunity Professor Tracy Hussell - - PowerPoint PPT Presentation

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Director, Lydia Becker Instjtute of Immunology and Infmammatjon University of Manchester, UK. Tracy.hussell@manchester.ac.uk

Decision making in lung immunity Professor Tracy Hussell

tracy.hussell@manchester.ac.uk

• Tissue complexity
• Homeostasis
• Normal processes that do not stop

Multjple factors afgectjng macrophage infmammatory tone

7 40 g No difference in 43 miRNAs let-7b 185 152 16 29c 425 221 29b 27a 378 93 24 324-5p 484 328 125a-5p 200b 450-5p 322 503 1 3 11 Fold change 0.2 0.8 1

B

Fold change d

d

ResolvedAMP NiaveAMP

Rik Ch 15: Ch X:

70bp 50401332 50407161 50407432 5740bp 201bp

E

85537033 622bp 85537749 99bp 94bp

let-7c2

94bp 84bp

let-7b 450a

Naive Resolved

Blind folding airway macrophages: miRNA modifjcatjons

Dr Alexander Godlee

The impact of the extracellular matrix

• n infmammatjon. Lydia Sorokin

Nature Reviews Immunology volume 10, pages 712–723 (2010)000

collagen type XVIII alpha 1 chain Nephronectjn: binds integrin a8b1

The instructjve extracellular matrix of the lung: basic compositjon and alteratjons in chronic lung disease Gerald Burgstaller, Bettjna 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 Fibronectjn X-linked fjbrillar collagen Basal membrane Hyaluronan Myofjbroblast Tenascin C Integrins Fibroblast

Hyaluronan is a major constjtuent of the infmamed lung

Why does matrix persist? Productjon versus degradatjon

Digestjon of HA restores lung functjon

Hyaluronidase at d15 afuer infmuenza

Mechanosensing podosomes exert a protrusive force that senses environment stjfgness

F-actjn-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 actjn 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

mono MDM AMΦ C D 3 6 B A I 1 T I M 1 T I M 3 T I M 4 A x l M e r T K T y r

• 3

25 50 250 500 relative mRNA expression MDM Actin Axl MerTK AMΦ

Difgerentjal 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 defectjve efgerocytosis in asthma. J Allergy Clin Immunol. 2017 Apr 12. (17)30585-7.

Cell death: A double edged sword in lung repair

HD asthma 0.0 0.5 1.0 1.5 ** extracellular nucleosome [A405] AMΦ HD asthma 101 102 103 104 *** sputum HD asthma 10-2 10-1 100 101 ** relative sAxl levels [a.u.]

Apoptotjc sensing by lung basal cells

Multjtasking basal cells: combining stem cell and innate immune dutjes. Shaykhiev R. Eur Respir J. 2015 Oct;46(4):894-7

P63 Survivin DAPI Symmetric Asymmetric P63 Survivin 8 days post infm uenza infection

Basal cells respond to local cues: apoptotjc cells AXL drives basal cell proliferatjon

Rock JR, Randell SH, Hogan BL. Dis Model Mech. 2010 Sep-Oct;3(9-10):545-56. Airway basal stem cells: a perspectjve 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 difgerentjatjon. Distant members of the TGF-β superfamily

Neurturin infmuences infmammatory responses and airway remodeling in difgerent mouse asthma models.

Maufgray 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 afgected equally

Dr Sylvia Liu

Most variable genes that defjne these clusters

Bind CXCR2 Recruits Mono and neuts IFN-response gene Induces apoptosis In same group as IFITM3/M2

Where are the opportunitjes? Health at difgerent life stages What 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 defjcits in infants?

Matched for sex and ethnicity All healthy diagnosis

Dr Anu Goenka Prof Peter Arkwright

Restoring tjssue physiology to limit “infmammatory” disease

Infmamed tjssues or trapped infmammatory 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 Liu Dr Dave Morgan Dr Emma Connolly Dr Anu Goenka Dr Ben Mulhearn Dr Chris Jagger Jakub Chudziak Dr Christjne Chew Dr Oliver Bland Mirium Franklin Sarah Warbach

Past members: Dr Alek Grabiec Dr Naoya Fujino Dr Toshifumi Fujimori Dr Tom Bell Dr Manminder Kaur Dr Samira Salek-Ardakani Dr Mark Fife Dr Lauren Cholewa Dr Maryam Habibzay Dr Alexandra Godlee Dr John Goulding Dr Robert Sanders Dr Robert Snelgrove

Clinical colleagues: Professor Angela Simpson Professor Stephen Fowler Professor Rob Niven Professor Jurgen Vestbo