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Importance of TLR2 in Early Innate Immune Response to Acute Pulmonary Infection with Porphyromonas gingivalis in Mice¹

George Hajishengallis^2,*,, Min Wang^*, Gregory J. Bagby^,,¶ and Steve Nelson^,,¶

^* Department of Periodontics/Oral Health & Systemic Disease and Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40292; and Section of Pulmonary and Critical Care Medicine, Alcohol Research Center, and ^¶ Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA 70112

The periodontal pathogen Porphyromonas gingivalis is implicated in certain systemic diseases including atherosclerosis and aspiration pneumonia. This organism induces innate responses predominantly through TLR2, which also mediates its ability to induce experimental periodontitis and accelerate atherosclerosis. Using a validated mouse model of intratracheal challenge, we investigated the role of TLR2 in the control of P. gingivalis acute pulmonary infection. TLR2-deficient mice elicited reduced proinflammatory or antimicrobial responses (KC, MIP-1, TNF-, IL-6, IL-12p70, and NO) in the lung and exhibited impaired clearance of P. gingivalis compared with normal controls. However, the influx of polymorphonuclear leukocytes into the lung and the numbers of resident alveolar macrophages (AM) were comparable between the two groups. TLR2 signaling was important for in vitro killing of P. gingivalis by polymorphonuclear leukocytes or AM and, moreover, the AM bactericidal activity required NO production. Strikingly, AM were more potent than peritoneal or splenic macrophages in P. gingivalis killing, attributed to diminished AM expression of complement receptor-3 (CR3), which is exploited by P. gingivalis to promote its survival. The selective expression of CR3 by tissue macrophages and the requirement of TLR2 inside-out signaling for CR3 exploitation by P. gingivalis suggest that the role of TLR2 in host protection may be contextual. Thus, although TLR2 may mediate destructive effects, as seen in models of experimental periodontitis and atherosclerosis, we have now shown that the same receptor confers protection against P. gingivalis in acute lung infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by United States Public Health Service Grants DE015254 and DE018292 (to G.H.) and AA09803 (to S.N. and G.J.B.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. George Hajishengallis, University of Louisville Health Sciences Center, 501 South Preston Street, Room 206, Louisville, KY 40292. E-mail address: g0haji01{at}louisville.edu

³ Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; AM, alveolar macrophage; CR3, complement receptor-3; DPI, diphenylene iodonium; L-NAME, N^G-nitro-L-arginine methyl ester; D-NAME, N^G-nitro-D-arginine methyl ester; BALF, bronchoalveolar lavage fluid; MPO, myeloperoxidase; NO₂^–, nitrite; MOI, multiplicity of infection; DCFH-DA, 2',7'-dichlorofluorescin diacetate; iNOS, inducible nitric oxide synthase.