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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis

Authors: Ngiambudulu M. Francisco, Nai-Jen Hsu, Roanne Keeton, Philippa Randall, Boipelo Sebesho, Nasiema Allie, Dhirendra Govender, Valerie Quesniaux, Bernhard Ryffel, Lauriston Kellaway, Muazzam Jacobs

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear.

Methods

We generated neuron-specific TNF-deficient (NsTNF−/−) mice and compared outcomes of disease against TNFf/f control and global TNF−/− mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA).

Results

Intracerebral M. tuberculosis infection of TNF−/− mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF−/− mice were resistant to infection and presented with a phenotype similar to that in TNFf/f control mice. Impaired immunity in TNF−/− mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx.

Conclusion

Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB.
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Metadata
Title
TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis
Authors
Ngiambudulu M. Francisco
Nai-Jen Hsu
Roanne Keeton
Philippa Randall
Boipelo Sebesho
Nasiema Allie
Dhirendra Govender
Valerie Quesniaux
Bernhard Ryffel
Lauriston Kellaway
Muazzam Jacobs
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0345-1

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