Transcript Il1rl2 +/+ Il1rl2

The complex role of IL-36γ
during intestinal inflammation
Oscar Medina
DISCLOSURES
• Nothing to disclose
Intestinal Immune System
Annu. Rev. Immunol. 27:313
Healthy and Inflamed Intestine LP MΦ
Healthy
Intestine
Inflamed
Intestine
Ly6C
CX3CR1
CCR2
IL-10
CD45+IAb+
CD11b+F4/80+
CD45+IAb+
CD11b+F4/80+
Resident Mφ
Infiltrating Mφ
TNFα
Retinoic acid
Immunity 14:1076
Mucosal Immunol. 6:498
Resident
Infiltrating
80
60
40
20
0
CTL
DSS
50
43
40
30
20
10
0
4.8 3.1
2.0 1.4 1.4 1.4 1.3 1.3 1.1 1.0
Il 3
Il 2 6 g
Il 1 3 a
2a
Il6
I l1
I l38
I l13
Il 3 a
6b
I
Il3 l1b
6r
Il 3 n
6a
100
Colitic/healthy cLP Mf
mRNA (fold)
Frequency
(% of total cLP Mf)
IL-36γ is expressed by Ly6C+ inflammatory LP Mø
D
R
Bh
i
20
IL-36g (pg/ml)
40
IL-36α
IL-36β
20
15
*
*
5
*
0
IL-36g mRNA expression
(/gapdh x10-4)
60
H
.h
ep
.
45
SS
10
C
TL
IL-36 mRNA expression
(/gapdh x10-3)
0
D
C
IL-36γ mRNA expression
(fold)
IL-36γ is expressed during
experimental colitis and human IBD
*
20
ND
IL-36γ
1
*
15
10
5
0
CTL
100
HC
DSS
10
*
*
*
IBD
UC
CD
8
*
6
4
2
0
CTL
IL-36g
IL-23R mRNA (fold)
IL-23 mRNA (fold)
IL-36γ induces IL-23 and IL-23R in vivo
15
*
10
5
0
CTL
IL-36g
IL-36γ promotes Th17/22 and inhibits Foxp3+ T cells
400
IL-22 (pg/ml)
IL-17A (pg/ml)
60
40
20
0
PBS
IL-36γ
*
300
200
100
0
PBS
IL-36γ
Loss of IL-36R ameliorates DSS colitis
+/+
Il1rl2
Il1rl2-/-
100
*
50
2
*
1
0
0
*
*
Il1rl2+/+
* * *
0
1
2
3
Time (d)
4
Il1rl2+/+
Il1rl2-/-
250
IL-23 (pg/ml)
DAI
3
IL-17A (pg/ml)
150
5
200
150
50
0
Il1rl2-/-
*
100
Il1rl2+/+
Il1rl2-/-
30
20
6
400
IL-22 (pg/ml)
IL-36γ
IL-22
4
2
0
0
1
2
3
4
300
200
100
0
5
4
3
Il1rl2+/+
Il1rl2-/-
Il1rl2+/+
Il1rl2-/-
1
0
*
** *
*
2
*
**
*
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time (d)
*
*
Time (d)
DAI
mRNA expression
(/gapdh x10-4)
IL-36R signaling induces IL-22
5
IL-22 (% of IL-36g)
IL-36 promotes mucosal healing/repair
via the AhR/IL-22 axis
100
80
*
60
*
40
*
*
20
ND ND
*
*
D
C
:T
IL
-3
6γ
IL
-1
8
IL
-3
3
IL
IL
-3 1β
6γ
+R
a
0
4
DAI
3
Il1rl2+/+ FICZ
Il1rl2-/- FICZ
Il1rl2+/+
Il1rl2-/-
2
Il1rl2+/+
Il1rl2+/+ FICZ
Il1rl2-/-
Il1rl2-/- FICZ
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time (d)
Summary
Injury Phase
Resolution Phase
S100A Reg3β
IL-22
ROS
Nφ
Nφ
RORγt
Th22
DC
Mφ
Treg
IL-36γ
Induced by bacterial components
Promotes Th1/17 responses
Inhibits iTreg differentiation
Th1
ILC
RORγt
?
?
Th17
Exacerbates DSS colitis
IL-36γ
Promotes healing/repair
Activates AhR
Induces IL-22
Acknowledgements
Tim Denning
Duke Geem
Charles Parkos
Asma Nusrat
Ifor Williams
Aaron Rae
Funding:
Jennifer Towne