TLR2 Deficiency Leads to Increased Th17 Infiltrates in Experimental Brain Abscesses

Abstract

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-␥-positive cells. ␥␦ 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-␣ 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.

T and B Cells Are Not Required for ClearingStaphylococcus aureusin Systemic Infection Despite a Strong TLR2–MyD88-Dependent T Cell Activation

“…The suppressive effect of IFN-g on T H 2 development (46) might be the reason for undetectable IL-4, and the IFN-gmediated inhibition of T H 17 cell differentiation might explain the low levels of IL-17 cells (47)(48)(49). In line with this hypothesis, the TLR2-pathway activated by S. aureus was also associated with reduced proportions of IL-17-producing CD4 + T cells in immune cells surrounding brain abscesses (50). However, in the current study, production of IL-17 may have been supported by high quantities of the proinflammatory cytokine IL-6, possibly together with TGF-b and amplified by high levels of TNF and IL-1b in S. aureus-infected DCs (51).…”

TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

“…However, the regulatory effects of TLR2 on Th17 cells have appeared to be contradictory in various studies. In pulmonary fungal infection and brain abscess, TLR2 was reported to act as a negative regulator for Th17 cells (24,37), whereas in experimental autoimmune encephalomyelitis, skin inflammation, and tuberculosis infection, TLR2 was reported to have the opposite effect (38)(39)(40). These findings suggest that the specific effect of TLR2 on Th17 cells varies with the type of immune response and depends on the microenvironment of the target tissues.…”

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

“…More recent studies on the role of TLR2 in localized infections in vivo have revealed a much more complex interaction between TLR2 and microbial pathogens. In a murine model of S. aureus brain abscess, TLR2 deficiency was associated with the increased infiltration of IL-17 producing T cells to the lesions [24]. Similarly, in Paracoccidioides brasiliensis infection of the lung, TLR2 À/À mice displayed a Th17 phenotype that was associated with impaired expansion of regulatory CD4 1 CD25 1 Foxp3 1 T cells [25].…”