Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, 45071 Orleans, France.
Sci Rep. 2016 Dec 20;6:39499. doi: 10.1038/srep39499.
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 mice. Without exacerbated lung inflammation, we found a compensatory increase in p75TNFR shedding and decrease in bioactive TNF in BAL of p55 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.
肿瘤坏死因子（TNF）的多效性活性是由两种结构相关但功能不同的 I 型跨膜受体介导的，这两种受体在大多数细胞类型中表达，即 p55TNFR 和 p75TNFR，它们可以被切割并作为 TNF 的清除剂。在这里，我们研究了在吸入有毒结核分枝杆菌 H37Rv 气溶胶挑战期间持续表达 p55TNFR 对细胞表面的影响。我们证明，在巨噬细胞培养物中 p55TNFR 的持续存在增加了可溶性 TNF、p75TNFR 和 NO 的合成，但对细菌杀伤能力没有影响。此外，它并没有促进 p55 小鼠对原发性急性结核分枝杆菌感染的保护作用。在没有加重肺部炎症的情况下，我们发现 p55 小鼠在结核分枝杆菌感染后 BAL 中的 p75TNFR 脱落增加和生物活性 TNF 减少。由于在持续表达 p55TNFR 期间 T 细胞反应受损，导致慢性感染期间短暂易感性增加，导致 CD44 和 INFγ 的表达缺陷。此外，持续表达 p55TNFR 可诱导潜伏性结核感染的早期再激活。这些数据表明，p55TNFR 脱落在 Th1 介导的慢性和潜伏性结核感染保护中起重要作用。
