Decision making in lung immunity Professor Tracy Hussell tracy.hussell@manchester.ac.uk Director, Lydia Becker Instjtute of Immunology and Infmammatjon University of Manchester, UK. Tracy.hussell@manchester.ac.uk • Tissue complexity • Homeostasis • Normal processes that do not stop 1
Multjple factors afgectjng macrophage infmammatory tone
Blind folding airway macrophages: miRNA modifjcatjons B let-7b Naive Resolved NiaveAMP ResolvedAMP 185 11 152 16 29c 425 E 221 94bp 84bp 29b 622bp Ch 15: let-7c2 let-7b Fold change 27a 1 378 7 Rik 85537749 No difference in 43 miRNAs 85537033 93 0.8 70bp 99bp 94bp 201bp 5740bp 24 Ch X: 450a 324-5p 40 484 g 50407161 50407432 50401332 328 125a-5p 0.2 200b 450-5p 0 1 3 Fold change 322 503 d d Dr Alexander Godlee
collagen type XVIII Nephronectjn: binds alpha 1 chain integrin a 8 b 1 The impact of the extracellular matrix on infmammatjon. Lydia Sorokin Nature Reviews Immunology volume 10, pages 712–723 (2010)000
X-linked Basal fjbrillar membrane Fibrillar collagen Fibronectjn Hyaluronan collagen Fibroblast Tenascin C Myofjbroblast Integrins 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
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
Cell death: A double edged sword in lung repair 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.
Difgerentjal expression of TAM receptors on human macrophage subsets mono 500 MDM AMΦ relative mRNA expression MDM AMΦ Axl 250 MerTK 50 Actin 25 0 M C T B T T T A e y D I I I A M M M r r x o 3 I T 1 l 1 3 4 3 6 K 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 sputum AMΦ ** relative sAxl levels [a.u.] 104 101 *** 100 103 10-1 102 10-2 101 extracellular nucleosome [A 405 ] HD asthma HD asthma 1.5 ** 1.0 0.5 0.0 HD asthma
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 P63 Survivin DAPI Symmetric Basal cells respond to local cues: Asymmetric apoptotjc cells 8 days post infm uenza infection AXL drives basal cell proliferatjon
Basal cell hyperplasia 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.
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 Human Bronchial epithelial cells (Beas-2b) Emma Connolly
Not all cells are afgected equally Dr Sylvia Liu
Most variable genes that defjne these clusters IFN-response gene Induces apoptosis Bind CXCR2 In same group as IFITM3/M2 Recruits Mono and neuts
Where are the opportunitjes? Health at difgerent life stages What drives change?
Do the same pathways explain immune defjcits in infants? Infants Adults (n=20) (n=20) Matched for sex and ethnicity All healthy diagnosis 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 10 5 ), median 2.9 (1.8-18) 2.35 (1.2-13) 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 Past members: Dr Dave Morgan Dr Emma Connolly Dr Alek Grabiec Dr Naoya Fujino Dr Anu Goenka Dr Toshifumi Fujimori Dr Ben Mulhearn Dr Tom Bell Dr Chris Jagger Dr Manminder Kaur Jakub Chudziak Dr Samira Salek-Ardakani Dr Christjne Chew Dr Mark Fife Dr Oliver Bland Dr Lauren Cholewa Mirium Franklin Sarah Warbach Dr Maryam Habibzay Dr Alexandra Godlee Clinical colleagues: Dr John Goulding Dr Robert Sanders Professor Angela Simpson Dr Robert Snelgrove Professor Stephen Fowler Professor Rob Niven Professor Jurgen Vestbo
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