Parenchymal cell TNF receptors contribute to inflammatory cell recruitment and respiratory failure in Pneumocystis carinii-induced pneumonia.
The opportunistic organism Pneumocystis carinii (Pc) produces a life-threatening pneumonia (PcP) in patients with low CD4(+) T cell counts. Animal models of HIV-AIDS-related PcP indicate that development of severe disease is dependent on the presence of CD8(+) T cells and the TNF receptors (TNFR) TNFRsf1a and TNFRsf1b. To distinguish roles of parenchymal and hematopoietic cell TNF signaling in PcP-related lung injury, murine bone marrow transplant chimeras of wild-type, C57BL6/J, and TNFRsf1a/1b double-null origin were generated, CD4(+) T cell depleted, and inoculated with Pc. As expected, C57 --> C57 chimeras (donor marrow --> recipient) developed significant disease as assessed by weight loss, impaired pulmonary function (lung resistance and dynamic lung compliance), and inflammatory cell infiltration. In contrast, TNFRsf1a/1b(-/-) --> TNFRsf1a/1b(-/-) mice were relatively mildly affected despite carrying the greatest organism burden. Mice solely lacking parenchymal TNFRs (C57 --> TNFRsf1a/1b(-/-)) had milder disease than did C57 --> C57 mice. Both groups of mice with TNFR-deficient parenchymal cells had low bronchoalveolar lavage fluid total cell counts and fewer lavageable CD8(+) T cells than did C57 --> C57 mice, suggesting that parenchymal TNFR signaling contributes to PcP-related immunopathology through the recruitment of damaging immune cells. Interestingly, mice with wild-type parenchymal cells but TNFRsf1a/1b(-/-) hematopoietic cells (TNFRsf1a/1b(-/-) --> C57) displayed exacerbated disease characterized by increased MCP-1 and KC production in the lung and increased macrophage and lymphocyte numbers in the lavage, indicating a dysregulated immune response. This study supports a key role of parenchymal cell TNFRs in lung injury induced by Pc and a potential protective effect of receptors on radiosensitive, bone marrow-derived cells.
Pryhuber
Gloria S
GS
Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA. gloria_pryhuber@urmc.rochester.edu
Huyck
Heidie L
HL
Bhagwat
Samir
S
O'Reilly
Michael A
MA
Finkelstein
Jacob N
JN
Gigliotti
Francis
F
Wright
Terry W
TW
D000818:Animals; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006836:Hydro-Lyases / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D018183:Transplantation Chimera
D018124:Receptors, Tumor Necrosis Factor; D006836:Hydro-Lyases; C045581:lactate dehydratase