Toll-Like Receptor 4-Positive Macrophages Protect Mice from Pasteurella pneumotropica -Induced Pneumonia

Abstract

ABSTRACT This study investigates Toll-like receptor 4 (TLR4)-positive macrophages in early recognition and clearance of pulmonary bacteria. TLR4 is a trans -membrane receptor that is the primary recognition molecule for lipopolysaccharide of gram-negative bacteria. The TLR4 Lps-del mouse strains C57BL10/ScN (B10) and STOCK Abb tm1 TLR4 Lps-del Slc11a1 s (B10 × C2D) are susceptible to pulmonary infections and develop pneumonia when naturally or experimentally infected by the opportunistic bacterium Pasteurella pneumotropica. Since these mice have the TLR4 Lps-del genotype, we hypothesized that reconstitution of mice with TLR4-positive macrophages would provide resistance to this bacterium. A cultured macrophage cell line (C2D macrophages) and bone marrow cells from C2D mice were adoptively transferred to B10 and B10 × C2D mice by intraperitoneal injection. C2D macrophages increased B10 and B10 × C2D mouse resistance to P. pneumotropica . In C2D-recipient mice there was earlier transcription of tumor necrosis factor alpha and chemokines JE and macrophage inflammatory protein 2 (MIP-2) in the lungs of B10 and B10 × C2D mice, and there was earlier transcription of KC and MIP-1α in B10 × C2D mice. In addition, the course of inflammation following experimental Pasteurella challenge was altered in C2D recipients. C2D macrophages also protected B10 × C2D mice, which lack CD4 + T cells. These data indicate that macrophages are critical for pulmonary immunity and can provide host resistance to P. pneumotropica. This study indicates that TLR4-positive macrophages are important for early recognition and clearance of pulmonary bacterial infections.