Inflammation and extracellular proteinases
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1 Inflammation and extracellular proteinases
2 Plaque rupture 75% of MI (heart attack) Foamy macrophages Thin cap No collagen Thin fibrous cap (<65 µm), large lipid core, no collagen, macrophages, T-cells Davies, M Circulation 1996; Falk, E JACC 2006;47:C7-12
3 Long-term consequences of MI Cardiac rupture Heart failure Scar Scar Too little Inflammation/ repair stanfordhospital.org Too much inflammation
4 van der Wal Cardiovasc Res 1999;41: Foam cells make proteases that cause plaque vulnerability Foam cells Low collagen
5 Metalloproteinases and TIMPs 23 MMPs Many non-matrix substrates Numbers TIMPs1-4 MMPs 1,8,13 MMPs (2),9 MMPs 3,7,10,11 MMP 12,19 MMPs 14-7,23,25 MMP class Interstitial collagenases Gelatinases (A),B Stromelysins Metalloelastase + Membrane-type MMPs
6 Inflammation and macrophage diversity M1 M-CSF GM-CSF M2 LPS, CD40L TNFα, IL-1 IFNγ IL-4 IL-13 Invasion Phagocytosis Killing Ox-LDL? Exit from lesions Antigen presentation Fibrosis, Calcification Angiogenesis Gordon S, Taylor PR. Nat Rev Immunol. 2005;5(12):
7 Effect of foam cell formation Spann et al. Cell 2012; 151,
8 Are all mouse models of atherosclerosis Dinosaurs?
9 Many biochemical differences HDL rather than LDL SAA rather than CRP MMP-13 rather than MMP-1 Transcript Levels of MMPs/TIMPs in Mouse vs Human Macrophages 1,E+08 1,E+07 1,E+06 1,E+05 1,E+04 1,E+03 1,E+02 1,E+01 1,E+00 Mouse Blood Macrophages Human Mo Macrophages Human M1 Macrophages Human M2 Macrophages Many MMP/TIMPs showed 10-10,000 fold Δ
10 Macrophage phenotypes the future
11 David Hockney Follow the pathways!
12 MCSF, GMCSF and OxLDL Old name M-Mac GM-Mac Foam cell Proposed name MM(-CSF) MGM(-CSF) FM(OxLDL) CSFR1/CD115 CSFR2/CD116 Scavenger Rs Signal 1 ERKs, PI-3K ERKs, PI-3K Free cholesterol, desmosterol TFs Pu.1, Egr-1 AP-1 Pu.1, Egr-1 AP-1, STAT-5 LXRα,β SREBPs Markers CD206 CD206 CD11c, Foamy appearance Proposed marker Nuclear STAT-5P Adipophilin 1 2 3
13 Classical activation pathways LPS TNFα IL-1 Production of interferons TRAF MyD88 TRIF
14 Classical activation pathways LPS TNFα IL-1 IFNs TRAF MyD88 TRIF JAK-2 STAT1 STAT1
15 Classically-activated (M1) phenotypes Proposed name MTNFα MCD30L /CD40L /Ox40L MIL-1 MLPS (TLL) Receptor TNFRSF IL1R1 TLR-4 (TLRs) Signal 1 TRAFs Myd88 Myd88 IRF-3 MIFNγ IFNγR1 Jak1/2, IRF-3 (M1) MLPS +IFNγ All Signal 2 ERKs, PI3K, PKC, IKK2 STAT-1 All TFs AP-1, NF-κB STAT-1 All Markers? IκB, COX-2, inos IL12, TLR4, CD14 Proposed Nuclear NF-κB Nuclear marker STAT1-P Both Both 4 5 6
16 Huang, Sala-Newby et. al. unpublished Compare Huang, Sala-Newby et. al. PLoS ONE 2012 Human Foam cells stimulated by LPS + IFNγ in vitro (M1) Copy numbers / ng RNA COX M0 M1 M MMP MMP MMP M0 M1 M2 M0 M1 M2 M0 M1 M2
17 Compare Huang, Sala-Newby et. al. PLoS ONE 2012 Human foam cells stimulated by LPS + IFNγ (M1) in vitro Copy numbers / ng RNA COX M0 M1 M MMP M0 M1 M MMP M0 M1 M MMP M0 M1 M2
18 10000 Effects of classical activators 1000 Fold change LPS IL-1 TNF IFN 1 0,1 MMP-1 MMP-10 MMP-12 MMP-14 TIMP-3 COX-2 IKB Huang, Sala-Newby et. al. PLoS ONE 2012
19 LPS on MAP and IkB kinases Pretreat p42-44 ERK(p) P42-44 ERK p38(p) DMSO LPS PD SB SP SC IkBa GAPDH LPS p38 JNK(p) JNK
20 Effect of inhibitors on LPS 10 Ratio vs no inhibitor 1 0,1 0,01 0,001 0,0001 MMP12 MMP1 MMP3 MMP10 MEKi p38i JNKi IKK2i PI3ki Huang, Sala-Newby and Newby, PLoS One 2012
21 A. CD68 MMP-1 COX-2 MMP-1 COX2 A. CD68 MMP10 NF-kB MMP-10 NF-kB Huang, Sala-Newby and Newby, PLoS One 2012
22 70 Percent of CD68 positive cells MMP-1 vs COX-2 MMP-1 vs NF-kB MMP-10 vs COX-2 MMP-10 vs NF-kB 0 Double positive First positive Second positive Double negative Huang, Sala-Newby and Newby, PLoS One 2012
23 MMP-14 and NF-kB NF-kB MMP-14 DUAL + DAPI Johnson, Jenkins et al, unpublished Percentage of MT1-MMP Positive FCMs Nuclear NFkB Cytoplasmic NFkB Negative
24 Role of TLR2 Monaco C. Circulation. 2009;120(24):
25 Effect of JAK-2 inhibitor on IFNγ Percentage of IFNg alone DMSO DMSO + 20 microm IFN IFN + 20 microm MMP-12 MMP-14 MMP-25 TIMP-3 COX-2 SOCS-3 Huang, Sala-Newby and Newby, PLoS One 2012
26 Conclusions 1 M1 genes are regulated through NFκB in vitro and co-localize in vivo A subgroup may co-localize with Stat-1P (to be shown)
27 Ingram JL, Journal of Allergy and Clinical Immunology. 2012;130:
28 Alternatively-activated (M2) phenotypes Old name M2a M2b M2c Fibrocyte Proposed MIL4/13 MNHR MIL10 MTGFβ name Receptor IL-4RF GCR, PPAR, Nur77 IL10R TGFβRI/II TFs Markers Proposed marker STAT-6, KLF4 CD206, COX- 1, maf-1 Nuclear STAT6-P NHR STAT-3 SMADs2/3 FosB CD163 CD163 Collagen, fibronectin Nuclear SMAD2-P
29 Compare Huang, Sala-Newby et. al. PLoS ONE 2012 Foam cells stimulated by IL-4 (M2) Copy numbers / ng RNA CD M0 M1 M MMP M0 M1 M MMP M0 M1 M TIMP M0 M1 M2
30 mrna level relative to UT IL4 2 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 MMP-12 CD206 P-STAT-6 P-DNSTAT-6 STAT-6 DNSTAT-6 MMP-12 medium GAPDH extract Sala-Newby and Newby, unpublished
31 TIMP-3 and CD206 CD206 TIMP DUAL + DAPI Percentage of Positive FCMs Johnson, Jenkins et al, unpublished 0 Dual TIMP3/CD206 TIMP3 CD206
32 A pstat-6 NI control pstat-6 Johnson and Newby, unpublished
33 Genomic studies on hypoxic macrophages y/cor.nb?id=12481#corp=13%2 C10%2C Gene fold change SERPINB ANKRD IL1A IL1B LRRC CA CXCL MMP MMP MMP MMP y/cor.nb?id=8415 Gene fold change DDIT ADM 52.2 SLC2A TSPAN NR4A MT1X 18.7 NEFL 15.6 GSTA2 15 RGS IL MMP
34 Hypoxia and MMP mrnas in vitro Fold vs normoxia Effect of hypoxia Effect of hypoxia MMP-1 MMP C TNF IL1 LPS Hyp TNF IL1 LPS Normoxia Hypoxia Sala-Newby, et al, unpublished
35 Hypoxia induced MMP-12 protein independent of Stat-6 MMP-12 pstat-6 STAT-6 Ratio of protein levels IL Hypoxia Hypoxia/ normoxia (n=4) Hypoxia IL-4 Hypoxia + IL-4 Sala-Newby et al, unpublished
36 Phenotypes related to oxidation Name Mox Mhem Mhypox Receptor ScavengerRs CD163 Signal 1 ROS ROS HIF1/2α, ERKs, IKK2, PI3K, wnts TFs Nrf2, low NF-κB Nrf2, ATF-1, low NF-κB HIF1/2α, NF-κB, TCF/Lef Markers HO-1 HO-1, CD163, VEGF, Glut-1 Low MHCII Proposed marker?? Nuclear HIF1α
37 Conclusions 2 M2 genes are regulated through Stat-6 in vitro but do not necessarily colocalize in vivo There are a lot more definable phenotypes than M1 and M2 Follow the pathways to greater wisdom!
38 Thanks Buket Reel Graciela Newby David Huang
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