| First Author | Deepe GS Jr | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 1 | Pages | 334-44 |
| PubMed ID | 22102723 | Mgi Jnum | J:180361 |
| Mgi Id | MGI:5306164 | Doi | 10.4049/jimmunol.1102175 |
| Citation | Deepe GS Jr, et al. (2012) Deciphering the pathways of death of Histoplasma capsulatum-infected macrophages: implications for the immunopathogenesis of early infection. J Immunol 188(1):334-44 |
| abstractText | Apoptosis of leukocytes is known to strongly influence the immunopathogenesis of infection. In this study, we dissected the death pathways of murine macrophages (MPhis) infected with the intracellular pathogen Histoplasma capsulatum. Yeast cells caused apoptosis of MPhis at a wide range of multiplicity of infection, but smaller inocula resulted in delayed detection of apoptosis. Upon infection, caspases 3 and 1 were activated, and both contributed to cell death; however, only the former was involved in apoptosis. The principal driving force for apoptosis involved the extrinsic pathway via engagement of TNFR1 by TNF-alpha. Infected MPhis produced IL-10 that dampened apoptosis. The chronology of TNF-alpha and IL-10 release differed in vitro. The former was detected by 2 h postinfection, and the latter was not detected until 8 h postinfection. In vivo, the lungs of TNFR1(-/-) mice infected for 1 d contained fewer apoptotic MPhis than wild-type mice, whereas the lungs of IL-10(-/-) mice exhibited more. Blockade of apoptosis by a pan-caspase inhibitor or by simvastatin sharply reduced the release of TNF-alpha but enhanced IL-10. However, these treatments did not modify the fungal burden in vitro over 72 h. Thus, suppressing cell death modulated cytokine release but did not alter the fungal burden. These findings provide a framework for the early pathogenesis of histoplasmosis in which yeast cell invasion of lung MPhis engenders apoptosis, triggered in part in an autocrine TNF-alpha-dependent manner, followed by release of IL-10 that likely prevents apoptosis of newly infected neighboring phagocytes. |
