Impaired recognition by Toll-like receptor 4 is responsible for exacerbated murine Pneumocystis pneumonia.
We investigated the effect of Toll-like receptor 4 (TLR4) on the progression of murine Pneumocystis pneumonia. TLR4-mutant C3H/HeJ and wild-type C3H/HeN mice were infected with Pneumocystis after depletion of CD4 T cells. Mutant mice lost body weight more quickly and showed exacerbated pulmonary injury even though there was no difference in Pneumocystis organism burden in the lung. Mutant mice showed reduced levels of IL-10, IL-12p40 and MIP-2 accompanied by elevated levels of TNF-alpha and IL-6 in the bronchoalveolar lavage fluid compared with those of wild-type mice 8 weeks after the infection. In response to stimulation with Pneumocystis antigen, the production of IL-10, IL-12p40 and MIP-2 by alveolar macrophages was partially impaired in mutant mice, while that in wild-type mice was suppressed by the anti-TLR4/MD-2 mAb, MTS510. Unlike the response to lipopolysaccharide stimulation, TLR4-reconstituted HEK293 cells showed no elevated NF-kappaB activation after stimulation with Pneumocystis antigen. Taken together, these findings suggest that recognition of Pneumocystis by TLR4 helps to regulate the host inflammatory responses through cytokine and chemokine production by alveolar macrophages.
Ding
Kai
K
Division of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan.
Shibui
Akiko
A
Wang
Yi
Y
Takamoto
Masaya
M
Matsuguchi
Tetsuya
T
Sugane
Kazuo
K
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D011010:Pneumocystis / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors