Angiogenesis in Viral Immunoinflammatory Lesions
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Angiogenesis in Viral Immunoinflammatory Lesions Barry T. Rouse University of Tennessee Part 3
description
Angiogenesis in Viral Immunoinflammatory Lesions. Barry T. Rouse University of Tennessee Part 3. A second mechanism could involve signalling molecules made early after HSV infection IL-6 and IL-1 (Most cell genes turned off by infection). - PowerPoint PPT Presentation
Transcript of Angiogenesis in Viral Immunoinflammatory Lesions
Angiogenesis in Viral Immunoinflammatory
LesionsBarry T. Rouse
University of Tennessee
Part 3
A second mechanism could involve signalling molecules made early after HSV infection–IL-6 and IL-1 (Most cell genes
turned off by infection)
• IL-6 administration into the corneal stroma causes angiogenesis
• The effect is prevented by anti-VEGF
IL-6 induces angiogenesis by up regulating VEGF production in the cornea
VEGF164
PBS
IL-6
IL-6 +
anti-mVEGF
Days post injection1 2 3 4 5 6 7 8
Ang
ioge
nic
area
(mm
2 )
0.0
0.5
1.0
1.5
2.0
2.5IL-6 200ngVEGF 200ngIL-6 + anti-VEGF
VEGF ELISA VEGFR2 Real Time PCR
IL-1 upregulates VEGF and VEGFR2 expression in corneas following HSV-1 infection
Days p.i.1 2 3 4 5 6 7 8
pg/c
orne
a
0
10
20
30
40
50
60
70
Days p.i.naive 2 5 7
copi
es/c
orne
a
0
10000
20000
30000
40000
50000
60000
IL-1Ra TgIL-1Ra KOC57BL/6
IL-1Ra Tg
IL-1Ra K/O
C57BL6
Blocking IL-1 activity reduces corneal angiogenesis following HSV-1 infection
Ang
ioge
nesi
s sc
ore
2 4 6 8 10 12 14 16 18 20 2202468
1012141618
Days p.i.
IL-1Ra TgIL-1Ra K/OC57BL6
HSV Infection
Autocrine production of signaling molecules
(IL-6, IL-1)
Induction of VEGFMIP-2 Signal
PMN
MMP-9
Corneal Neovascularization
Possible role of MMP-9 in stromal keratitis
(serves to degrade matrix so vessels can proceed into the stroma)
HSV infection causes MMP-9 upregulation2 days post infection
MMP-9
MMP-2
UV viru
sMutan
t (ICP-4-
/-)
WT viru
s (KOS)
WT v
irus (
RE)tra
uma
naive
Histo
Anti MMP-9
Infected corneas have MMP-9 expressing cells
MMP-9
MMP-2
Neutrophils are a likely source of MMP-9
Anti G
r-1Con
trol Ig
G
0
5
10
15
20
Ang
ioge
nic
scor
ing
0 5 10 15 20Days post infection
MMP-9 K/O129 Sv/Ev WT
0
1
2
3
4
5
Seve
rity
0 5 10 15 20
MMP-9 KO mice show diminished angiogenesis and severity of HSK
0
5
10
15
20
Ang
ioge
nic
scor
ing
0 5 10 15 20
TIMP-1 DNAvector DNA
0
1
2
3
4
5
Seve
rity
0 5 10 15 20
Days post infection
Effect of MMP-9 inhibitor, TIMP-1, on HSV induced angiogenesis
HSV induced angiogenesis involves multiple factors. These include VEGF, FGF (not shown), MIP-2 (not shown), and MMP-9
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