Parenchymal Cell TNF Receptors Contribute to Inflammatory Cell Recruitment and Respiratory Failure in Pneumocystis carinii-Induced Pneumonia (original) (raw)
Related papers
The Journal of Immunology, 2008
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 3 C57 chimeras (donor marrow 3 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 ؊/؊ 3 TNFRsf1a/1b ؊/؊ mice were relatively mildly affected despite carrying the greatest organism burden. Mice solely lacking parenchymal TNFRs (C57 3 TNFRsf1a/ 1b ؊/؊ ) had milder disease than did C57 3 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 3 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 ؊/؊ 3 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.
The Journal of Immunology, 2004
CD8 ؉ T cells contribute to the pathophysiology of Pneumocystis pneumonia (PcP) in a murine model of AIDS-related disease. The present studies were undertaken to more precisely define the mechanisms by which these immune cells mediate the inflammatory response that leads to lung injury. Experimental mice were depleted of either CD4 ؉ T cells or both CD4 ؉ and CD8 ؉ T cells and then infected with Pneumocystis. The CD4 ؉ -depleted mice had significantly greater pulmonary TNF-␣ levels than mice depleted of both CD4 ؉ and CD8 ؉ T cells. Elevated TNF-␣ levels were associated with increased lung concentrations of the chemokines RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant. To determine whether TNFR signaling was involved in the CD8 ؉ T cell-dependent chemokine response, TNFRI-and II-deficient mice were CD4 ؉ depleted and infected with Pneumocystis. TNFR-deficient mice had significantly reduced pulmonary
Journal of Immunology, 2004
CD8 ؉ T cells contribute to the pathophysiology of Pneumocystis pneumonia (PcP) in a murine model of AIDS-related disease. The present studies were undertaken to more precisely define the mechanisms by which these immune cells mediate the inflammatory response that leads to lung injury. Experimental mice were depleted of either CD4 ؉ T cells or both CD4 ؉ and CD8 ؉ T cells and then infected with Pneumocystis. The CD4 ؉-depleted mice had significantly greater pulmonary TNF-␣ levels than mice depleted of both CD4 ؉ and CD8 ؉ T cells. Elevated TNF-␣ levels were associated with increased lung concentrations of the chemokines RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant. To determine whether TNFR signaling was involved in the CD8 ؉ T cell-dependent chemokine response, TNFRI-and II-deficient mice were CD4 ؉ depleted and infected with Pneumocystis. TNFR-deficient mice had significantly reduced pulmonary RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant responses, reduced inflammatory cell recruitment to the alveoli, and reduced histological evidence of PcP-related alveolitis as compared with infected wild-type mice. Diminished pulmonary inflammation correlated with improved surfactant activity and improved pulmonary function in the TNFR-deficient mice. These data indicate that TNFR signaling is required for maximal CD8 ؉ T cell-dependent pulmonary inflammation and lung injury during PcP and also demonstrate that CD8 ؉ T cells can use TNFR signaling pathways to respond to an extracellular fungal pathogen.