Genetic ablation of IRAK4 kinase activity inhibits vascular lesion formation.
Inflammation is critically involved in atherogenesis. Signaling from innate immunity receptors TLR2 and 4, IL-1 and IL-18 is mediated by MyD88 and further by interleukin-1 receptor activated kinases (IRAK) 4 and 1. We hypothesized that IRAK4 kinase activity is critical for development of atherosclerosis. IRAK4 kinase-inactive knock-in mouse was crossed with the ApoE-/- mouse. Lesion development was stimulated by carotid ligation. IRAK4 functional deficiency was associated with down-regulation of several pro-inflammatory genes, inhibition of macrophage infiltration, smooth muscle cell and lipid accumulation in vascular lesions. Reduction of plaque size and inhibition of outward remodeling were also observed. Similar effects were observed when ApoE-/- mice subjected to carotid ligation were treated with recombinant IL-1 receptor antagonist thereby validating the model in the relevant pathway context. Thus, IRAK4 functional deficiency inhibits vascular lesion formation in ApoE-/- mice, which further unravels mechanisms of vascular inflammation and identifies IRAK4 as a potential therapeutic target.
Rekhter
Mark
M
Lilly Research Laboratories, Lilly Corporate Center DC1705, Indianapolis, IN 46285, USA.
Staschke
Kirk
K
Estridge
Thomas
T
Rutherford
Pamela
P
Jackson
Nancy
N
Gifford-Moore
Donetta
D
Foxworthy
Patricia
P
Reidy
Charles
C
Huang
Xiao-di
XD
Kalbfleisch
Michael
M
Hui
Kwan
K
Kuo
Ming-Shang
MS
Gilmour
Raymond
R
Vlahos
Chris J
CJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D002097:C-Reactive Protein / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014654:Vascular Patency / Q000187:drug effects / Q000235:genetics
D001057:Apolipoproteins E; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D002097:C-Reactive Protein; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse