Key role of TLR2 in the inflammatory response and MHC-II down-regulation in Brucella-infected alveolar macrophages

Abstract

Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of TNF-α, KC, IL-1β, IL-6 and IL-12 in AM from C57BL/6 mice and Balb/c mice, but these responses were generally weaker and/or delayed as compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4 and TLR9 revealed that TNF-α and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a MOI-dependent manner the expression of MHC-II molecules induced by gamma-interferon (IFN-γ) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19 kDa outer membrane protein of Brucella (L-Omp19), and was shown to be mediated by TLR2 recognition. In contrast, no significant down-regulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intra-tracheal infection viable B. abortus was detected in AM from both wild type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus may survive in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival.