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Myeloid Differentiation Protein-2–Dependent and –Independent Neutrophil Accumulation during Escherichia coli Pneumonia

¹ Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University (LSU), Baton Rouge, Louisiana; ² Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado; ³ Department of Medicine, National Jewish Health, Denver, Colorado; and ⁴ Section of Pulmonary and Critical Care Medicine, Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana

Correspondence and requests for reprints should be addressed to Samithamby Jeyaseelan, D.V.M., Ph.D., LSU, Baton Rouge, LA 70803. E-mail: jey{at}lsu.edu or worthen{at}email.chop.edu

Bacterial pneumonia remains a serious disease. Pattern recognition receptors play an integral role in neutrophil accumulation during pneumonia. Although myeloid differentiation protein (MD)-2 has been recognized as a key molecule for LPS signaling, the role of MD-2 in neutrophil accumulation in the lung during bacterial infection has not been explored. Here, we investigate the role of MD-2 in Escherichia coli LPS–induced lung inflammation and E. coli–induced pneumonia. LPS-induced CD14-independent neutrophil accumulation was abolished in CD14/MD-2^–/– mice. MD-2^–/– mice challenged with LPS displayed attenuated neutrophil influx, NF-B activation, cytokine/chemokine expression, and lung histopathology. MD-2^–/– mice transplanted with MD-2^+/+ bone marrow demonstrated decreased neutrophil influx and cytokine/chemokine expression in the lungs when challenged by LPS. MD-2^–/– mice infected with E. coli demonstrated reduced neutrophil influx and cytokine/chemokine expression in the lungs, whereas heat-killed E. coli did not induce either neutrophil accumulation or cytokine/chemokine expression in MD-2^–/– mice infected with E. coli. Furthermore, MD-2^–/– mice displayed increased bacterial burden in the lungs and enhanced bacterial dissemination. Toll-like receptor (TLR)-5^–/– mice infected with E. coli exhibited attenuated neutrophil accumulation, whereas MD-2/TLR5^–/– mice inoculated with E. coli showed further attenuated neutrophil influx and impaired bacterial clearance. Taken together, these new findings demonstrate: (1) the important role of MD-2 in the CD14-independent LPS-mediated cascade of neutrophil influx; (2) the relative importance of bone marrow– and non–bone marrow cell–derived MD-2 in LPS-induced inflammation; and (3) the essential role of MD-2–dependent and MD-2–independent (TLR5) signaling in E. coli–induced neutrophil accumulation and pulmonary host defense.

Key Words: neutrophil • host defense • mouse model

CLINICAL RELEVANCE This study will improve our understanding of the pathogenesis of bacterial pneumonia and help design improved treatment strategies.

 

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