Mycobacterium tuberculosis lipids regulate cytokines, TLR-2/4 and MHC class II expression in human macrophages

Rocha-Ramirez, Luz María; Estrada-Garcı́a, Iris; López-Marı́n, Luz M.; Segura-Salinas, Erika; Méndez-Aragón, Patricia; Soolingen, Dick van; Torres-González, R; Chacón‐Salinas, Rommel; Estrada‐Parra, Sergio; Maldonado‐Bernal, Carmen; López-Macías, Constantino; Isibasí, Armando

doi:10.1016/j.tube.2007.10.003

Cited by 72 publications

(56 citation statements)

References 61 publications

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“…Specifically, many tumors as well rely on the induction of IL-10 and other immune suppressive cytokines to dampen type 1 immune responses and to remain immune evasive. 65 In a fashion similar to that of the tumor, although it is believed that mycobacteria may simultaneously use multiple mechanisms of immune evasion including mechanisms of down-regulating antigen presentation, 42,61 in the current study we have shown that IL-10 is one of the essential mechanisms through which the immune suppressive environment of mycobacterial granuloma is maintained. Despite the overwhelming evidence to support a direct role of mycobacterial infection in inducing IL-10 production by APCs, [37][38][39]62 it is plausible for us to consider the possibility that some level of IL-10 may be actively induced as part of host immune regulatory mechanisms as a means to limit immunopathology, a concession that could be exploited by mycobacteria and has recently been suggested by others.…”

Section: Discussionmentioning

confidence: 56%

“…11,12,42,52 Furthermore, the critical role of type 1 T-cell immunity, including the role of CD4 T cells and type 1 cytokines in antimycobacterial host defense, has shown to be true for pulmonary infection elicited by exposure to either BCG or M.tb. 11,12,[53][54][55][56][57] M. bovis BCG also uss similar immune evasion strategies as M.tb to dampen host immune activation mechanisms including intracellular persistence, 58 -60 inhibiting MHC molecule expression, 42,61 and inducing IL-10 production. [37][38][39]62 Despite these described similarities, we must caution that, compared with Immunosuppression of Bacterial Granuloma 1631 AJP April 2011, Vol.…”

Section: Discussionmentioning

confidence: 99%

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Pulmonary Mycobacterial Granuloma

Shaler

Kugathasan

McCormick

et al. 2011

The American Journal of Pathology

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The granuloma, a hallmark of host defense against pulmonary mycobacterial infection, has long been believed to be an active type 1 immune environment. However, the mechanisms regarding why granuloma fails to eliminate mycobacteria even in immune-competent hosts, have remained largely unclear. By using a model of pulmonary Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, we have addressed this issue by comparing the immune responses within the airway luminal and granuloma compartments. We found that despite having a similar immune cellular profile to that in the airway lumen, the granuloma displayed severely suppressed type 1 immune cytokine but enhanced chemokine responses. Both antigen-presenting cells (APCs) and T cells in granuloma produced fewer type 1 immune molecules including tumor necrosis factor-␣ (TNF-␣), interferon-␥ (IFN-␥), and nitric oxide. As a result, the granuloma APCs developed a reduced capacity to phagocytose mycobacteria and to induce T-cell proliferation. To examine the molecular mechanisms, we compared the levels of immune suppressive cytokine IL-10 in the airway lumen and granuloma and found that both granuloma APCs and T cells produced much more IL-10. Thus, IL-10 deficiency restored type 1 immune activation within the granuloma while having a minimal effect within the airway lumen. Hence, our study provides the first experimental evidence that, contrary to the conventional belief, the BCG-induced lung granuloma represents a symbiotic host-microbe microenvironment characterized by suppressed type 1 immune activation.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Pulmonary Mycobacterial Granuloma

Shaler

Kugathasan

McCormick

et al. 2011

The American Journal of Pathology

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“…It is noteworthy that mycobacteria cell wall lipids disperse or shed upon association with the host cell or an appropriate environment within the macrophage (5). M. tuberculosis lipids have been profiled (3), and several of these mycobacterial lipids found across species have been reported to be involved in the immunosuppression of PBMC proliferation (6), modulation of cytokines (7,8), and exacerbation of the granulomatous response (9,10). It has been reported that M. tuberculosis lipids contribute to the virulence of the bacteria by inactivating host bactericidal enzymes and that tissue-specific localization of the lipids leads to increased pathogenicity (11,12).…”

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confidence: 99%

Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

Dkhar

Nanduri

Mahajan

et al. 2014

The Journal of Immunology

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The cell wall of Mycobacterium tuberculosis is configured of bioactive lipid classes that are essential for virulence and potentially involved in the formation of foamy macrophages (FMs) and granulomas. Our recent work established crosstalk between M. tuberculosis cell wall lipids and the host lipid-sensing nuclear receptor TR4. In this study, we have characterized, identified, and adopted a heterologous ligand keto-mycolic acid from among M. tuberculosis lipid repertoire for the host orphan NR TR4. Crosstalk between cell wall lipids and TR4 was analyzed by transactivation and promoter reporter assays. Mycolic acid (MA) was found to transactivate TR4 significantly compared with other cell wall lipids. Among the MA, the oxygenated form, keto-MA, was responsible for transactivation, and the identity was validated by TR4 binding assays followed by TLC and nuclear magnetic resonance. Isothermal titration calorimetry revealed that keto-MA binding to TR4 is energetically favorable. This keto-MA–TR4 axis seems to be essential to this oxygenated MA induction of FMs and granuloma formation as evaluated by in vitro and in vivo model of granuloma formation. TR4 binding with keto-MA features a unique association of host nuclear receptor with a bacterial lipid and adds to the presently known ligand repertoire beyond dietary lipids. Pharmacologic modulation of this heterologous axis may hold promise as an adjunct therapy to frontline tuberculosis drugs.

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“…Additional evidence demonstrates that M. tuberculosis utilizes its lipid moieties to modify the innate response of macrophages via TLR receptors. Differing virulence phenotypes of M. tuberculosis contain a different composition of lipids from one another, and infection with each strain results in opposing macrophage inflammatory phenotypes, with the most virulent strains more negatively affecting the TLR-activated cytokine response within the host phagocytes (Rocha-Ramírez et al, 2008). Keeping each of these situations in mind, the variation of bacterial lipids described in this study may provide a method of camouflage for the bacterium early during infection, by interacting with TLRs and cellular receptors and resulting in the alteration, by either suppression or stimulation, of the host immune response.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the inflammatory phenotype of Mycobacterium avium subspecies paratuberculosis using a novel cell culture passage model

et al. 2015

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Understanding the pathogenic mechanisms of Mycobacterium avium subspecies paratuberculosis (MAP) and the host responses to Johne's disease is complicated by the multi-faceted disease progression, late-onset host reaction and the lack of available ex vivo infection models. We describe a novel cell culture passage model that mimics the course of infection in vivo. The developed model simulates the interaction of MAP with the intestinal epithelial cells, followed by infection of macrophages and return to the intestinal epithelium. MAP internalization triggers a minimal inflammatory response. After passage through a macrophage phase, bacterial reinfection of MDBK epithelial cells, representing the late phase of intestinal mucosal infection, is associated with increased synthesis of the pro-inflammatory transcripts of IL-6, CCL5, IL-8 and IL-18, paired with decreased levels of TGFb. Transcriptome analysis of MAP from each stage of epithelial cell infection identified increased expression of lipid biosynthesis and lipopeptide modification genes in the inflammatory phenotype of MAP. Total lipid analysis by HPLC-ES/MS indicates different lipidomic profiles between the two phenotypes and a unique set of lipids composing the inflammatory MAP phenotype. The presence of selected upregulated lipid-modification gene transcripts in samples of ileal tissue from cows diagnosed with Johne's disease supports and validates the model. By using the relatively simple cell culture passage model, we show that MAP alters its lipid composition during intracellular infection and acquires a pro-inflammatory phenotype, which likely is associated with the inflammatory phase of Johne's disease.

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Mycobacterium tuberculosis lipids regulate cytokines, TLR-2/4 and MHC class II expression in human macrophages

Cited by 72 publications

References 61 publications

Pulmonary Mycobacterial Granuloma

Pulmonary Mycobacterial Granuloma

Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

Characterization of the inflammatory phenotype of Mycobacterium avium subspecies paratuberculosis using a novel cell culture passage model

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