TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease.
BACKGROUND
Kawasaki disease is the most common cause of acquired cardiac disease and acute vasculitis in children, targets the coronary arteries, and can occasionally be fatal. The pathogenesis and the molecular mechanisms remain unknown. After injection of Lactobacillus casei cell-wall extract (LCCWE), mice develop a focal coronary arteritis that histopathologically resembles Kawasaki disease, but the mechanism remains unclear. Here, we tested the hypothesis that signaling by Toll-like receptors (TLRs) through their key downstream adaptor molecule myeloid differentiation factor 88 (MyD88) is required for the cellular activation and coronary arteritis produced by LCCWE.


RESULTS
Bone marrow-derived macrophages from TLR2- or MyD88-deficient mice were unresponsive to LCCWE-induced stimulation. In contrast, macrophages obtained from TLR4-deficient mice produced the same amount of interleukin-6 as macrophages from wild-type mice after stimulation with LCCWE. Intraperitoneal injection of LCCWE produced severe focal coronary arteritis in TLR4(-/-) and C57BL/6 control mice but not in TLR2(-/-) or MyD88(-/-) mice. Collectively, these results indicate that LCCWE is a potent inducer of nuclear factor-kappaB via TLR2 but not TLR4 and that this activation proceeds via the MyD88-dependent signaling pathway. In vivo studies suggest that TLR2(-/-) mice are protected from LCCWE-induced coronary arteritis and that this protection is mediated through the adaptor molecule MyD88.


CONCLUSIONS
Our results provide important insights into the molecular signaling in this mouse model of coronary arteritis. We show here that LCCWE-induced coronary arteritis is dependent on intact TLR2 and MyD88 signaling.
Rosenkranz
Margalit E
ME
Pediatric Rheumatology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY, USA.
Schulte
Danica J
DJ
Agle
Lucila M A
LM
Wong
Michelle H
MH
Zhang
Wenxuan
W
Ivashkiv
Lionel
L
Doherty
Terence M
TM
Fishbein
Michael C
MC
Lehman
Thomas J A
TJ
Michelsen
Kathrin S
KS
Arditi
Moshe
M
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002457:Cell Extracts; D002473:Cell Wall; D002648:Child; D003327:Coronary Disease / Q000139:chemically induced / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D007780:Lacticaseibacillus casei; D051379:Mice; D009080:Mucocutaneous Lymph Node Syndrome / Q000503:physiopathology*; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2 / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002457:Cell Extracts; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2