FOXO3 Transcription Factor Regulates IL-10 Expression in Mycobacteria-Infected Macrophages, Tuning Their Polarization and the Subsequent Adaptive Immune Response

Bouzeyen, Rania; Haoues, Meriam; Barbouche, Mohamed‐Ridha; Singh, Ramandeep; Essafi, Makram

doi:10.3389/fimmu.2019.02922

Cited by 31 publications

(24 citation statements)

References 57 publications

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“…The inhibition of FOXO3 after TLR4 activation typically results in suppressed autophagy ( 82 ). In addition, AKT-dependent inhibition of FOXO3 through phosphorylation enhances the production of the anti-inflammatory cytokine IL-10 ( 83 ). Therefore, decreased FOXO3-phosphorylation would suppress IL-10 levels.…”

Section: Discussionmentioning

confidence: 99%

Non-Genomic AhR-Signaling Modulates the Immune Response in Endotoxin-Activated Macrophages After Activation by the Environmental Stressor BaP

et al. 2021

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Emerging studies revealed that the Aryl hydrocarbon receptor (AhR), a receptor sensing environmental contaminants, is executing an immunomodulatory function. However, it is an open question to which extent this is achieved by its role as a transcription factor or via non-genomic signaling. We utilized a multi-post-translational modification-omics approach to examine non-genomic AhR-signaling after activation with endogenous (FICZ) or exogenous (BaP) ligand in endotoxin-activated (LPS) monocyte-derived macrophages. While AhR activation affected abundances of few proteins, regulation of ubiquitination and phosphorylation were highly pronounced. Although the number and strength of effects depended on the applied AhR-ligand, both ligands increased ubiquitination of Rac1, which participates in PI3K/AKT-pathway-dependent macrophage activation, resulting in a pro-inflammatory phenotype. In contrast, co-treatment with ligand and LPS revealed a decreased AKT activity mediating an anti-inflammatory effect. Thus, our data show an immunomodulatory effect of AhR activation through a Rac1ubiquitination-dependent mechanism that attenuated AKT-signaling, resulting in a mitigated inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Non-Genomic AhR-Signaling Modulates the Immune Response in Endotoxin-Activated Macrophages After Activation by the Environmental Stressor BaP

et al. 2021

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“…Furthermore, according to the review by Wang et al, FOXO3 protects against oxidative stress by increasing the transcription of MnSOD , CAT , and peroxiredoxin III ( PRX3 ), and is also critical to hematopoietic self-renewal [ 125 ]. In the macrophages of old mice, the decrease in FOXO3 protein with age caused a loss of anti-inflammatory phenotype, whereas the PI3K/Akt/FOXO3 axis triggered by Mycobacterium tuberculosis suppressed transcription of IL10 and promoted a pro-inflammatory response in phagocytes, as reviewed by Stefanetti et al [ 126 , 127 ]. FOXO3 was reported as a target for PARP1-mediated ADP-ribosylation, but the role of this modification in FOXO3 transcriptional activity is contradictory in the two available papers.…”

Section: Parp1 In Macrophages—its Role In Their Polarizationmentioning

confidence: 99%

The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors

Sobczak

Zyma

Robaszkiewicz

2020

Cells

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Modulation of PARP1 expression, changes in its enzymatic activity, post-translational modifications, and inflammasome-dependent cleavage play an important role in the development of monocytes and numerous subtypes of highly specialized macrophages. Transcription of PARP1 is governed by the proliferation status of cells at each step of their development. Higher abundance of PARP1 in embryonic stem cells and in hematopoietic precursors supports their self-renewal and pluri-/multipotency, whereas a low level of the enzyme in monocytes determines the pattern of surface receptors and signal transducers that are functionally linked to the NFκB pathway. In macrophages, the involvement of PARP1 in regulation of transcription, signaling, inflammasome activity, metabolism, and redox balance supports macrophage polarization towards the pro-inflammatory phenotype (M1), which drives host defense against pathogens. On the other hand, it seems to limit the development of a variety of subsets of anti-inflammatory myeloid effectors (M2), which help to remove tissue debris and achieve healing. PARP inhibitors, which prevent protein ADP-ribosylation, and PARP1‒DNA traps, which capture the enzyme on chromatin, may allow us to modulate immune responses and the development of particular cell types. They can be also effective in the treatment of monocytic leukemia and other cancers by reverting the anti- to the proinflammatory phenotype in tumor-associated macrophages.

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“…Therefore, it is well established that IL-10 represents one such regulatory mechanism that Mtb could exploit to establish a chronic infection. The production of IL-10 in Mtb-infected macrophages is primarily an evasion mechanism against antimycobacterial reactions ( 16 ). One major mechanism of Mtb killing is mediated by IFN-γ activation of macrophages, but it can be inhibited by IL-10, and by blocking phagosome maturation through STAT3 signaling, which promotes Mtb survival and growth ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium tuberculosis Rv2145c Promotes Intracellular Survival by STAT3 and IL-10 Receptor Signaling

et al. 2021

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Although Mycobacterium tuberculosis (Mtb) is an intracellular pathogen in phagocytic cells, the factors and mechanisms by which they invade and persist in host cells are still not well understood. Characterization of the bacterial proteins modulating macrophage function is essential for understanding tuberculosis pathogenesis and bacterial virulence. Here we investigated the pathogenic role of the Rv2145c protein in stimulating IL-10 production. We first found that recombinant Rv2145c stimulated bone marrow-derived macrophages (BMDMs) to secrete IL-10, IL-6 and TNF-α but not IL-12p70 and to increase the expression of surface molecules through the MAPK, NF-κB, and TLR4 pathways and enhanced STAT3 activation and the expression of IL-10 receptor in Mtb-infected BMDMs. Rv2145c significantly enhanced intracellular Mtb growth in BMDMs compared with that in untreated cells, which was abrogated by STAT3 inhibition and IL-10 receptor (IL-10R) blockade. Expression of Rv2145c in Mycobacterium smegmatis (M. smegmatis) led to STAT3-dependent IL-10 production and enhancement of intracellular growth in BMDMs. Furthermore, the clearance of Rv2145c-expressing M. smegmatis in the lungs and spleens of mice was delayed, and these effects were abrogated by administration of anti-IL-10R antibodies. Finally, all mice infected with Rv2145c-expressing M. smegmatis died, but those infected with the vector control strain did not. Our data suggest that Rv2145c plays a role in creating a favorable environment for bacterial survival by modulating host signals.

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FOXO3 Transcription Factor Regulates IL-10 Expression in Mycobacteria-Infected Macrophages, Tuning Their Polarization and the Subsequent Adaptive Immune Response

Cited by 31 publications

References 57 publications

Non-Genomic AhR-Signaling Modulates the Immune Response in Endotoxin-Activated Macrophages After Activation by the Environmental Stressor BaP

Non-Genomic AhR-Signaling Modulates the Immune Response in Endotoxin-Activated Macrophages After Activation by the Environmental Stressor BaP

The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors

Mycobacterium tuberculosis Rv2145c Promotes Intracellular Survival by STAT3 and IL-10 Receptor Signaling

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