Thrombopoietin Contributes to Neuronal Damage in Experimental Bacterial Meningitis

Abstract

Thrombopoietin (Tpo), which primarily regulates megakaryopoiesis, and its receptor (c-Mpl) are expressed in the brain, where Tpo exhibits proapototic effects on neurons. In the present study, we investigated the implication of Tpo in experimental pneumococcal meningitis. Following intrathecal infection with the encapsulated Streptococcus pneumoniae strain D39, we observed upregulation of Tpo mRNA expression at 12 h and 24 h in brain homogenates of wild-type C57BL/6 mice. c-Mpl mRNA expression was upregulated at 12 h and returned to baseline at 24 h. Compared to wild-type mice, mutants with homozygous Tpo receptor ablation (c-Mpl ؊/؊ ) displayed reduced microglial activation and neuronal apoptosis in the dentate gyrus. Concentrations of bacteria in blood or cerebrospinal fluid (CSF), as well as CSF pleocytosis, were not significantly different between wild-type and c-Mpl ؊/؊ mice. In human postmortem brain, Tpo protein was colocalized to macrophages during encephalitis. In murine primary microglia and RAW264.7 macrophages, upregulation of Tpo mRNA was induced by D39-conditioned medium but not by bacterial lipopeptide or by medium conditioned by pneumococcal mutants defective in hydrogen peroxide formation (⌬spxB) or pneumolysin (⌬pln). We conclude that Tpo acts as a mediator of neuronal damage in bacterial meningitis.

Multifaceted roles of thrombopoietin in hematopoietic stem cell regulation

“…We have also shown that Thpo is produced in the osteoblastic niche and that Mpl + HSCs reside closely to osteoblasts . Mature hematopoietic cells, such as macrophages, have also been reported as a source of Thpo production . Within the BM, we reported that mature megakaryocytes may produce Thpo and function as a niche .…”

“…31 Mature hematopoietic cells, such as macrophages, have also been reported as a source of Thpo production. 58 Within the BM, we reported that mature megakaryocytes may produce Thpo and function as a niche. 59 Both studies identified Thpo expression in osteoblasts and megakaryocytes using quantitative PCR and antibody detection.…”

Caspr1 is a host receptor for meningitis-causing Escherichia coli

“…In the animal models of E. coli meningitis, apoptosis of neurons was present in the dentate gyrus of the hippocampus 20 . Evidence from experimental meningitis caused by other CNS-infecting pathogens, such as Streptococcus pneumoniae 17 , 21 – 23 and group B Streptococcus 18 , 24 indicated that apoptosis is a major contributor to neuronal cell death. The molecular mechanism of neuronal apoptosis in bacterial meningitis remains poorly understood.…”

The biology of thrombopoietin and thrombopoietin receptor agonists

“…In addition, MAP kinase pathways are activated, which potentiate maturation. Finally, less well studied but equally important, are the antiapoptotic pathways that are activated [25][26][27]. As discussed next, TPO binding results in mitosis, endomitosis, maturation, and a wide variety of anti-apoptotic effects in megakaryocyte precursors and in megakaryocytes [6,28].…”