MyD88 deficiency results in tissue-specific changes in cytokine induction and inflammation in interleukin-18-independent mice infected with Borrelia burgdorferi.
Toll-like receptors (TLRs) play an important role in the control of infection with Borrelia burgdorferi. Deficiencies in TLR-2 or the shared TLR adapter molecule MyD88 have been shown to result in greatly increased bacterial burdens in mice. However, although in vitro studies have shown that the activation of TLR pathways by B. burgdorferi results in the release of inflammatory cytokines, studies in deficient mice have shown either no change or increased rather than decreased inflammation in infected animals. In this study, we looked at mechanisms to explain the increase in inflammation in the absence of MyD88. We found that MyD88-deficient mice infected with B. burgdorferi did not show increased inflammation at sites typically associated with Lyme disease (joints and heart). However, there was markedly increased inflammation in the muscles, kidneys, pancreas, and lungs of deficient animals. Muscle inflammation was typically seen perivascularly and perineuronally similar to that seen in infected humans. Chemotactic chemokines and cytokines were greatly increased in the muscle and kidneys of MyD88-deficient animals but not in the joints or heart tissue, suggesting that MyD88-independent pathways for recognizing B. burgdorferi and inducing these chemokines are present in the muscle and kidneys. Interleukin-18 signaling through MyD88 does not appear to play a role in either control of infection or inflammation.
Behera
Aruna K
AK
New England Medical Center, Box 41, 750 Washington St., Boston, MA 02111. lhu@tufts-nemc.org.
Hildebrand
Ethan
E
Bronson
Roderick T
RT
Perides
George
G
Uematsu
Satoshi
S
Akira
Shizuo
S
Hu
Linden T
LT
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000502:physiology; D000818:Animals; D025065:Borrelia burgdorferi / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D007249:Inflammation / Q000209:etiology* / Q000276:immunology; D020382:Interleukin-18 / Q000378:metabolism*; D007596:Joints / Q000166:cytology; D008193:Lyme Disease / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D009205:Myocarditis / Q000382:microbiology / Q000503:physiopathology
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D020382:Interleukin-18; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88