Abstract
Pleural tuberculosis is one of the most frequent forms of extra-pulmonary tuberculosis observed in patients infected with Mycobacterium tuberculosis. Tumor Necrosis Factor (TNF) is a crucial cytokine needed to control tuberculosis infection that remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may increase the risk of reactivation of latent infection resulting in overt pulmonary, pleural and extra-pulmonary tuberculosis. While TNF signaling is mainly considered pro-inflammatory, its requirement for the anti-inflammation process involved in the resolution of infection and tissue repair is less explored. Our study analyzes the role of TNF and TNF receptors in the control of the inflammatory process associated with Bacillus Calmette-Guérin (BCG)-induced pleurisy. This study shows that the absence of TNF causes exacerbated inflammation in the pleural cavity of BCG-infected mice which is controlled by the transmembrane TNF (tmTNF) expression. The lack of TNF is associated with an impaired cellular expression and shedding of TNFR2 in the pleural cavity. The presence of tmTNF restores the normal expression of TNFR2 on myeloid cells during BCG-induced pleurisy. We also show that absence of TNFR1 affects the expression of TNFR2 on pleural cells and inflammation in the pleural cavity of BCG-infected mice. In conclusion, tmTNF but not soluble TNF prevents pleural cavity inflammation leading to attenuation and the resolution of the inflammatory process caused by mycobacterial pleurisy in association with the expression of TNFR2 on myeloid cells.
Highlights
Tumor Necrosis Factor (TNF) is a pleiotropic cytokine exerting a large range of activities through its receptors, TNFR1 and TNFR2
We have reported that Bacillus Calmette-Guérin (BCG)-induced pleurisy is lethal in TNF KO and TNFR1TNFR2 KO mice [17]
We have already reported that TNFR1TNFR2 KO mice showed a similar number of myeloid and lymphoid cells than TNF KO mice in the pleural cavity following BCG-induced pleurisy [17]
Summary
Tumor Necrosis Factor (TNF) is a pleiotropic cytokine exerting a large range of activities through its receptors, TNFR1 and TNFR2. TNF is first synthetized as a transmembrane molecule (tmTNF) and cleaved by tumor necrosis factor-alpha converting enzyme (TACE) resulting in the soluble trimeric TNF molecule (solTNF). A majority of the TNF effector functions have been attributed to the solTNF form but many are mediated by tmTNF, especially when cell-to-cell contact interaction is involved. Both solTNF and tmTNF as well as the Lymphotoxin-alpha (LT-α) signal through TNFR1 and TNFR2 [1,2]. Soluble TNF receptors (solTNFRs) are present in the blood of healthy individuals and during pathological situations such as infection and cancer; the dramatically increased levels of solTNFRs correlate with disease severity [3,4]
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