The Role of the Various Monocyte Types in Atherothrombotic Disease Protective vs. Detrimental Effects and Therapeutic Implications Matthias Nahrendorf MGH Center for Systems Biology http://csb.mgh.harvard.edu/investigator/matthias_nahrendorf HARVARD MEDICAL SCHOOL
Healing following myocardial infarction matters Good healing MedicineNet.com Good prognosis Bad healing Circulation. 1993 Mar;87(3):755-63 5% chance of death in next
Monocyte/macrophage heterogeneity in myocardial infarction Swirski & Nahrendorf, Science 213;339:161-6
Monocytes/macrophages in atherosclerosis Swirski & Nahrendorf, Science 213;339:161-6
Impaired infarct healing after plaque rupture Atherosclerosis Blood monocytosis Recruitment Ly-6C hi Inflammatory cyto/chemokines (e.g. MPO, TNF-α) Protease activity (e.g. MMPs, cathepsins) Resolution of inflammation (e.g. reduced TGF-β) Infarct expansion LV dilation EF Collagen synthesis Heart Failure Circulation 21; 121:2437
Quality of healing Is there a window of therapeutic opportunity to intervene on inflammation post? vertex (coronary ligation in healthy wild-type mice) 3 patients on steroids 4 patients with high CD14 + CD16 blood levels 5 monocyte depleted mice 2,3 patients with blood monocytosis 6 splenectomized mice 1 apoe -/- with blood monocytosis 7 Inflammatory monocytes 1. Swirski & Nahrendorf, Science 29 2. van Amerongen, Am J Pathol 27 3. Nahrendorf & Swirski, JEM 29 4. Roberts, Circulation 1976 5. Tsujioka, JACC 29 6. Maekawa, JACC 22 7. Panizzi, JACC 29 Circulation 21; 121:2437
Mortality (%) White blood cell count associates with in-hospital mortality in infarct patients (n = 115,) Leukocyte count Coller et al., ATVB 25;25:658-67
No d1 d3 d5 d7 % of BrdU + HSC SUV Bone marrow Blood Spleen Destination tissue Long-term hematopoietic stem cell Short-term hematopoietic stem cell Common myeloid progenitor Granulocyte Macrophage progenitor Macrophage dendritic cell progenitor Monocyte Macrophage 18 No.4 12 6.2 FACS Bone Marrow. 18 F-FLT PET No Dutta et al., Cell Stem Cell 215
no Ly-6C hi monocytes/mg tissue (1 4 ) Monocytes in Spleen The spleen is a reservoir for monocytes after Organization Expression profile Behavioral activity vessel parenchyma splenic monocytes cluster in the subcapsular red pulp Monocytes in Blood splenic monocytes resemble blood monocytes (99.998%) Pre injury Post injury Inflammation mobilizes monocytes in vivo Release Relocation Consequence 6 Pre + Spleen Spleen + Spleen Spleen 3 Ang II triggers release of monocytes into peripheral blood Before After.5 1 Day post The spleen contributes monocytes in infarct Released splenic monocytes participate in inflammation Science 29; 325:612
No Increase in protease activity (pmol) Ex vivo TBR FRI enhances protease activity in plaque Week Week 3 Week 3 3 7 15 4 1 No Dutta/Courties et al., Nature 212;487:325-9
Ly-6C high monocytes (1 3 ) / aorta Plaque size (mm 2 ) CD11b + area (mm 2 ) enhances monocyte/macrophage numbers in plaque No 6 3 No.6.2 2 3.4.2.1 Age (in weeks) Dutta/Courties et al., Nature 212;487:325-9
enhances atherosclerosis Swirski & Nahrendorf, Science 213;339:161-6
18 F-FDG uptake increases in atheroma, bone marrow, and spleen during acute Tawakol et al., ijacc 215
BrdU steady state non-infarcted parabiont non-infarcted parabiont CD48 % of BrdU + HSCs/femur C-kit Heart IL-1β mrna Infarct IL-1β (pg/ml) Blood IL-1β (pg/ml) Marrow IL-1β (pg/ml) Sager / Dutta Danger signals: IL-1β 2 15 25 2 75 125 1 1 5 no 24h 72h no 24h 72h no 24h 72h no 24h 72h steady state non-infarcted parabiont non-infarcted IL1R1 -/- parabiont 14d 3 days FACS 24 Sca-1 14d 3 days FACS 12 IL1R1 -/- CD15 IL1R1 -/- 14d IL1R1 -/- 3 days FACS CD15
BrdU % of BrdU+ HSCs/femur CD48 1 3 HSCs/femur C-kit 1 4 LSKs/femur Anti IL-1β therapy modulates hematopoiesis no + Ctrl IgG.54 + Ctrl IgG 2.29 + anti IL-1β 1.56 6 3 Sca-1 5 2.5 CD15 8.3 17.9 12.8 17.8 33.7 25.4 2 1 Sca-1 Sager / Dutta
F4/8 Ly6c high monocytes (x1 3 )/mg infarct Ly6c low monocytes (x1 3 )/mg infarct Lineage neutrophils (x1 3 )/mg infarct macrophages (x1 3 )/mg infarct Anti IL-1β therapy mutes inflammatory leukocytes during myocardial infarction + Ctrl IgG + anti IL-1β 1 5 3 15 CD11b 1 12 5 6 Ly6C Sager / Dutta
21 d after decrease in LVEF (%) 7 d after infarct protease activity (pmol) 1 d after infarct size (% of myocardium) Anti IL-1β therapy improves LV function post + Ctrl IgG + anti IL-1β 4 2 2 1 3 15 Sager / Tricot / Wojtkiewicz
Acknowledgements Fil Swirski Dan Anderson Chares Lin David Scadden Marcelo Di Carli David Sosnovik Ahmed Tawakol Willem Mulder Zahi Fayad Michael Moskowitz Ralph Weissleder Peter Libby Ned Keliher Maulik Majmudar Gabriel Courties Florian Leuschner Partha Dutta Hendrik Sager Felix Hoyer Gabriel Courties Fanny Herrison Yuxiang Ye Yoshiko Iwamoto Yuan Sun Kamila Naxerova csb.mgh.harvard.edu/nahrendorf HHSN2682144C, R1HL95629, R1HL96576, R1HL114477, R1HL117829 HARVARD MEDICAL SCHOOL