TLR2 Signal Is Protective In Periapical Lesion

Objective: We previously reported that TLR4 signal, which is triggered by Gram-negative bacteria, mediates infection-induced periapical bone loss. Although TLR2 triggers inflammation in response to Gram-positive bacteria, the role of TLR2 in periapical inflammation is still unclear. In the present study, we determined the functional role of TLR2 signal in polymicrobial infection-induced periapical bone loss using TLR gene deficient (^-/-) mice.

Method: TLR2^-/-, TLR2/TLR4^-/-, and C57BL/6 (WT) mice were employed. The dental pulps of the first molars were exposed and infected with a mixture of Prevotella intermedia, Fusobacterium nucleatum, Peptostreptococcus micros, and Streptococcus intermedius. Mice were sacrificed on days 0 (non-infected control) and 21 after pulpal infection. The extent of periapical bone loss was determined using micro computed tomography. Thioglycolate-elicited peritoneal macrophages were isolated from the mice above and stimulated with or without E. coli LPS (1µg/ml) and Pam2CSK4 (100ng/mL) for 16 hrs. Gene expression in macrophages was assessed by quantitative RT-PCR.

Result: The extent of infection-induced periapical bone loss in TLR2^-/- mice was significantly higher than other two strains on day 21 after pulpal infection (>2-fold; p<0.01), suggesting TLR2 signal appears to be protective in the development of periapical lesion. Since the extent of bone loss was similar in TLR2/TLR4^-/- and WT mice, the extended bone loss in TLR2^-/- seems to be mediated by TLR4 signal. In response to LPS/Pam2CSK4 stimulation, TLR4 signaling pathway including CD14, IRAK2, and RelB, but not TLR4, was significantly up-regulated in TLR2^-/- macrophages vs. WT cells (p<0.05). This finding suggests that signal cross-talk between TLR2 and TLR4 seems to regulate CD14/TLR4 complex formation and subsequent TLR4 signal.

Conclusion: TLR2 signal seems to be protective via suppression of TLR4 signal in the development of periapical bone loss.