TLR2 deficiency leads to increased Th17 infiltrates in experimental brain abscesses.
TLR2 plays a pivotal role in recognizing Staphylococcus aureus, a common etiologic agent of CNS parenchymal infections, such as brain abscess. We previously reported that brain abscesses of TLR2 knockout (KO) mice exhibited elevated IL-17 levels, suggesting the presence of an alternative pathway available to respond to S. aureus infection that may involve Th17 cells. Both CD4(+) and CD8(+) T cell infiltrates were elevated in brain abscesses of TLR2 KO mice at days 3, 7, and 14 postinfection compared with wild-type animals. Intracellular cytokine staining revealed a significant increase in the frequency of IL-17-producing Th17 cells in TLR2 KO mice with relatively few IFN-gamma-positive cells. gammadelta T cells were also a source of IL-17 in brain abscesses. Microglia, astrocytes, and macrophages were shown to express both IL-17RA and IL-17RC. Despite receptor expression, IL-17 was relatively ineffective at eliciting glial activation, whereas the cytokine augmented the ability of TNF-alpha to induce CXCL2 and CCL2 expression by macrophages. Based on the ability of IL-17 to elicit the release of chemokines and other proinflammatory mediators, we propose that the exaggerated IL-17 response that occurs in TLR2 KO mice functions in a compensatory manner to control brain abscess pathogenesis, with cells other than glia as targets for IL-17 action. This is supported by our findings in which innate immune infiltrates were not significantly different between TLR2 KO and wild-type mice in conjunction with the lack of prolonged alterations in the synthesis of other proinflammatory molecules during the course of infection.
Nichols
Jessica R
JR
Department of Pediatrics, Arkansas Children's Hospital, Little Rock, AR 72205, USA.
Aldrich
Amy L
AL
Mariani
Monica M
MM
Vidlak
Debbie
D
Esen
Nilufer
N
Kielian
Tammy
T
D000818:Animals; D001922:Brain Abscess; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000032:analysis; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D053722:Receptors, Interleukin-17; D013601:T-Lymphocytes / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency*
D016207:Cytokines; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D051195:Toll-Like Receptor 2