Mycobacteria Bypass Mucosal NF-kB Signalling to Induce an Epithelial Anti-Inflammatory IL-22 and IL-10 Response

Lutay, Nataliya; Håkansson, Gisela; Alaridah, Nader; Hällgren, Oskar; Westergren‐Thorsson, Gunilla; Godaly, Gabriela

doi:10.1371/journal.pone.0086466

Cited by 35 publications

(32 citation statements)

References 69 publications

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“…TNF) [36,37], while PI3K activation [through phosphorylation of protein kinase B (Akt), a downstream kinase] is associated with anti-inflammatory responses (e.g. with enhancement of IL-10 synthesis) [38]. As such, it is possible that reverse signalling through infliximab binding to transmembrane TNF generates monocytes that differentiate in vitro into macrophages with both pro-and anti-inflammatory markers.…”

Section: Cd16mentioning

confidence: 99%

Infliximab therapy increases the frequency of circulating CD16+ monocytes and modifies macrophage cytokine response to bacterial infection

Nazareth

Magro

Silva

et al. 2014

Clinical and Experimental Immunology

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SummaryCrohn's disease (CD) has been correlated with altered macrophage response to microorganisms. Considering the efficacy of infliximab treatment on CD remission, we investigated infliximab effects on circulating monocyte subsets and on macrophage cytokine response to bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, treated or not with infliximab. Macrophages were infected with Escherichia coli, Enterococcus faecalis, Mycobacterium avium subsp. paratuberculosis (MAP) or M. avium subsp avium, and cytokine levels [tumour necrosis factor (TNF) and interleukin (IL)-10] were evaluated at different time-points. To evaluate infliximab-dependent effects on monocyte subsets, we studied CD14 and CD16 expression by peripheral blood monocytes before and after different infliximab administrations. We also investigated TNF secretion by macrophages obtained from CD16 + and CD16 − monocytes and the frequency of TNF + cells among CD16 + and CD16 − monocyte-derived macrophages from CD patients. Infliximab treatment resulted in elevated TNF and IL-10 macrophage response to bacteria. An infliximab-dependent increase in the frequency of circulating CD16 + monocytes (particularly the CD14 ++ CD16 + subset) was also observed (before infliximab: 4·65 ± 0·58%; after three administrations: 10·68 ± 2·23%). In response to MAP infection, macrophages obtained from CD16 + monocytes were higher TNF producers and CD16 + macrophages from infliximab-treated CD patients showed increased frequency of TNF + cells. In conclusion, infliximab treatment increased the TNF production of CD macrophages in response to bacteria, which seemed to depend upon enrichment of CD16 + circulating monocytes, particularly of the CD14 ++ CD16 + subset. Infliximab treatment of CD patients also resulted in increased macrophage IL-10 production in response to bacteria, suggesting an infliximab-induced shift to M2 macrophages.

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Section: Cd16mentioning

confidence: 99%

Infliximab therapy increases the frequency of circulating CD16+ monocytes and modifies macrophage cytokine response to bacterial infection

Nazareth

Magro

Silva

et al. 2014

Clinical and Experimental Immunology

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“…IL-6, a pro-inflammatory cytokine and an important biomarker for AE-IPF (19), is stimulated by NF-κB (20). IL-10, an anti-inflammatory cytokine, inhibits inflammation by suppressing NF-κB expression and activity (21). In the current study, IL-10 peaked (day 35) 4 days later than IL-6 (day 31) and the IL6/IL10 ratio reduced gradually in the BLM + BLM group, indicating that the second perfusion induces dynamic inflammatory changes in the lung.…”

Section: Discussionmentioning

confidence: 99%

Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis

et al. 2017

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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with severe pulmonary fibrosis. The main cause of IPF-associated death is acute exacerbation of IPF (AE-IPF).This study aims to develop a rat model of AE-IPF by two intratracheal perfusions with bleomycin (BLM).Methods: Ninety male Sprague Dawley (SD) rats were randomized into three groups: an AE-IPF model group (BLM + BLM group), an IPF model group (BLM group), and a normal control group. Rats in the BLM + BLM group underwent a second perfusion with BLM on day 28 after the first perfusion with BLM.Rats in the other two groups received saline as the second perfusion. Six rats in each group were sacrificed on day 31, day 35, and day 42 after the first perfusion, respectively. Additional 18 rats in each group were observed for survival.Results: Rats in the BLM + BLM group had significantly worse pulmonary alveolar inflammation and fibrosis than rats in the BLM group. Rats in the BLM + BLM group also developed large amounts of hyaline membrane, showed high levels of albumin (ALB) and various inflammatory factors in the bronchoalveolar lavage fluid (BALF), and had markedly increased lung water content. Furthermore, rat survival was reduced in the BLM + BLM group. The pathophysiological characteristics of rats in the BLM + BLM group resemble those of patients with AE-IPF.Conclusions: A second perfusion with BLM appears to induce acute exacerbation of pulmonary fibrosis and may be used to model AE-IPF in rats.

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“…GSK3β plays a pivotal role in regulating many cellular functions, including cell survival and apoptosis (165, 178–180). M. bovis BCG induces phosphorylation of GSK3 by the PI3K–Akt signaling pathway, switching the transcriptional activity to an anti-inflammatory CREB-driven cytokine response instead of the pro-inflammatory NF-κB transcription (181, 182). GSK3β is an upstream kinase regulating PD-1 transcription, and the use of GSK3β inhibitors in vivo downregulates PD-1 and enhances CTL clearance of viral infections (183).…”

Section: Targeting Cell Regulatory Pathways and Immune Checkpoints Asmentioning

confidence: 99%

Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

Jayashankar

Hafner

2016

Front. Immunol.

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Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette–Guérin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity. This review provides an assessment of the known immunoregulatory mechanisms altered by Mtb, and how new interventions may reverse these effects. Examples include blocking of inhibitory immune cell coreceptor checkpoints (e.g., programed death-1). Conversely, immune mechanisms that strengthen immune cell effector functions may be enhanced by interventions, including stimulatory immune cell coreceptors (e.g., OX40). Modification of the activity of key cell “immunometabolism” signaling pathway molecules, including mechanistic target of rapamycin, glycogen synthase kinase-3β, wnt/β-catenin, adenosine monophosophate-activated protein kinase, and sirtuins, related epigenetic changes, and preventing induction of immune regulatory cells (e.g., regulatory T cells, myeloid-derived suppressor cells) are powerful new approaches to improve vaccine responses. Interventions to favorably modulate these components have been studied primarily in oncology to induce efficient antitumor immune responses, often by potentiation of cancer vaccines. These agents include antibodies and a rapidly increasing number of small molecule drug classes that have contributed to the dramatic immune-based advances in treatment of cancer and other diseases. Because immune responses to malignancies and to Mtb share many similar mechanisms, studies to improve TB vaccine responses using interventions based on “immuno-oncology” are needed to guide possible repurposing. Understanding the regulation of immune cell functions appropriated by Mtb to promote the imbalance between protective and pathogenic immune responses may guide the development of innovative drug-based adjunct approaches to substantially enhance the clinical efficacy of TB vaccines.

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Mycobacteria Bypass Mucosal NF-kB Signalling to Induce an Epithelial Anti-Inflammatory IL-22 and IL-10 Response

Cited by 35 publications

References 69 publications

Infliximab therapy increases the frequency of circulating CD16+ monocytes and modifies macrophage cytokine response to bacterial infection

Infliximab therapy increases the frequency of circulating CD16+ monocytes and modifies macrophage cytokine response to bacterial infection

Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis

Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

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