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PPE38-Secretion-Dependent Proteins of M. tuberculosis Alter NF-kB Signalling and Inflammatory Responses in Macrophages.

ABSTRACT: It was previously shown that secretion of PE-PGRS and PPE-MPTR proteins is abolished in clinical M. tuberculosis isolates with a deletion in the ppe38-71 operon, which is associated with increased virulence. Here we investigate the proteins dependent on PPE38 for their secretion and their role in the innate immune response using temporal proteomics and protein turnover analysis in a macrophage infection model. A decreased pro-inflammatory response was observed in macrophages infected with PPE38-deficient M. tuberculosis CDC1551 as compared to wild type bacteria. We could show that dampening of the pro-inflammatory response is associated with activation of a RelB/p50 pathway, while the canonical inflammatory pathway is active during infection with wild type M. tuberculosis CDC1551. These results indicate a molecular mechanism by which M. tuberculosis PE/PPE proteins controlled by PPE38 have an effect on modulating macrophage responses through NF-kB signalling.

SUBMITTER: Gallant J

PROVIDER: S-EPMC8284050 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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PPE38-Secretion-Dependent Proteins of M. tuberculosis Alter NF-kB Signalling and Inflammatory Responses in Macrophages.

Gallant James J Heunis Tiaan T Beltran Caroline C Schildermans Karin K Bruijns Sven S Mertens Inge I Bitter Wilbert W Sampson Samantha L SL

Frontiers in immunology 20210702

It was previously shown that secretion of PE-PGRS and PPE-MPTR proteins is abolished in clinical M. tuberculosis isolates with a deletion in the ppe38-71 operon, which is associated with increased virulence. Here we investigate the proteins dependent on PPE38 for their secretion and their role in the innate immune response using temporal proteomics and protein turnover analysis in a macrophage infection model. A decreased pro-inflammatory response was observed in macrophages infect ...[more]

PMID: 34276695

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Project description:BackgroundNeuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway.MethodsThe putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells.ResultsCPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells.ConclusionsThese results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation.

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PPE38-Secretion-Dependent Proteins of M. tuberculosis Alter NF-kB Signalling and Inflammatory Responses in Macrophages.

Publications

PPE38-Secretion-Dependent Proteins of <i>M. tuberculosis</i> Alter NF-kB Signalling and Inflammatory Responses in Macrophages.

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PPE38-Secretion-Dependent Proteins of M. tuberculosis Alter NF-kB Signalling and Inflammatory Responses in Macrophages.

Publications

PPE38-Secretion-Dependent Proteins of &lt;i&gt;M. tuberculosis&lt;/i&gt; Alter NF-kB Signalling and Inflammatory Responses in Macrophages.

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OmicsDI is part of the ELIXIR infrastructure

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PPE38-Secretion-Dependent Proteins of <i>M. tuberculosis</i> Alter NF-kB Signalling and Inflammatory Responses in Macrophages.