Abstract
The pleiotropic activities of TNF are mediated by two structurally related but functionally distinct type I transmembrane receptors, p55TNFR and p75TNFR expressed in most cell types, that can be cleaved and act as TNF scavengers. Here, we investigated the effect of persistent p55TNFR cell surface expression during aerosol inhalation challenge with virulent M. tuberculosis H37Rv. We demonstrated that persistency of p55TNFR in macrophage cultures increased the synthesis of soluble TNF, p75TNFR and NO, however, had no effects on bacteria killing ability. Furthermore, it did not facilitate enhanced protection to primary acute M. tuberculosis infection in p55∆NS mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55∆NS mice after M. tuberculosis challenge. Defective expressions of CD44 and INFγ attributed to an impaired T cell response during persistent p55TNFR expression that caused marginal transient susceptibility during chronic infection. Moreover, persistent p55TNFR expression induced early reactivation during latent tuberculosis infection. These data indicate a prominent role of p55TNFR shedding in Th1 mediated protection against chronic and latent tuberculosis infection.
Highlights
Tumor Necrosis Factor (TNF) gene deletion[21,22,23,24], p55TNFR gene deletion[16,25,26], and TNF neutralization studies[27,28] demonstrated TNF-TNFR signaling as critical for protective immunity against mycobacterial infections
We report here after M. tuberculosis aerosol exposure that p55∆NS mice expressing nonsheddable p55TNFR controlled acute infection similar to their wild type (WT) counterparts while they exhibited a transient loss of control during chronic infection and an increased susceptibility to reactivation of latent tuberculosis
TNFR shedding from cell surfaces coincides with the generation of TNF16,17; its functional significance being associated with the regulation of TNF mediated effects[35,36,37,38]
Summary
TNF gene deletion[21,22,23,24], p55TNFR gene deletion[16,25,26], and TNF neutralization studies[27,28] demonstrated TNF-TNFR signaling as critical for protective immunity against mycobacterial infections. Results Sustained p55TNFR surface expression in p55∆NS peritoneal elicited cells after M. tuberculosis infection. Thioglycollate elicited macrophages from WT mice or p55∆NS mice were exposed to M. tuberculosis H37Rv for 20 minutes and p55TNFR cell surface expression determined by flow cytometry.
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