Roles of Soluble and Membrane TNF and Related Ligands in Mycobacterial Infections: Effects of Selective and Non-selective TNF Inhibitors During Infection

García, Irene; Olleros, Maria-Luisa; Quesniaux, Valérie; Jacobs, Muazzam; Allie, Nasiema; Nedospasov, Sergei A.; Szymkowski, David E.; Ryffel, Bernhard

doi:10.1007/978-1-4419-6612-4_20

Cited by 29 publications

(26 citation statements)

References 91 publications

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“…Production of mediators involved in mycobacterial resistance, such as TNF-␣, IL-6, or NO, was also impaired in IL-36R Ϫ/Ϫ splenocytes. 38 Consistently, IL-36R Ϫ/Ϫ mice showed more severe lung pathology after BCG infection compared with WT mice, revealing an involvement of IL-36R signaling in host protection against intracellular bacterial infection. In view of previously described protective roles of IL-18 and IL-12 during mycobacterial infection in vivo, [39][40][41] the study of potential synergies or redundancies of IL-36 with these Th1 cytokines will be of great interest.…”

Section: Il-36 and T-cell Responses 3485mentioning

confidence: 72%

IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

Vigne

Palmer

Martin

et al. 2012

Blood

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191

190

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IntroductionThe interleukin-1 (IL-1) family of cytokines comprises 11 members, including IL-1␣, IL-1␤, IL-18, IL-33, and the recently renamed IL-36␣, ␤, ␥ (previously known as IL-1F6, IL-1F8, and IL-1F9). 1 All these cytokines use heterodimeric receptors for signaling. IL-1, IL-33, and IL-36 bind to specific receptor ␣-chains, which are IL-1RI for IL-1␣ and IL-1␤, T1/ST2 (also known as IL-33R) for IL-33, and IL-36R (previously termed IL-1Rrp2) for IL-36, and then recruit the same coreceptor IL-1R accessory protein (IL-1RAcP). IL-18 uses IL-18R␣ and the coreceptor IL-18R␤. On receptor binding, all IL-1 family cytokines activate similar intracellular signals, including NF-B and mitogenactivated protein kinase (MAPK) pathways. IL-1 receptor antagonist (IL-1Ra) and IL-36Ra (previously termed IL-1F5), 2 additional members of the IL-1 family, act as natural inhibitors for the biologic activities of IL-1 and IL-36, respectively. [2][3][4] IL-1␣, IL-1␤, IL-18, and IL-33 are produced by activated innate immune cells (neutrophils, monocytes, macrophages, and dendritic cells) and epithelial cells, and stimulate proinflammatory innate and adaptive immune responses. More specifically, these cytokines influence CD4 ϩ T-cell responses and their polarization into the different T helper (Th) subsets Th1, Th2, and Th17. IL-1 promotes the proliferation and survival of naive CD4 ϩ T cells and plays a critical role in Th17 differentiation. 5-9 IL-18 and IL-33 stimulate the polarization of CD4 ϩ T cells into Th1 and Th2, respectively,10 although the selectivity of these responses may be modulated by the cytokine environment. Consistently, Th1, Th2, and Th17 cells selectively express the IL-1 family cytokine receptors IL-18R␣, T1/ST2, and IL-1RI, respectively. 10 IL-36 cytokines and IL-36R are abundantly expressed by keratinocytes and other epithelial cell types. 4,[11][12][13] IL-36 plays a major role in mouse experimental skin inflammation and in human psoriasis both in the initiation and regulation of inflammatory responses. [14][15][16][17][18][19] Furthermore, the association of a form of generalized pustular psoriasis with genetic IL-36Ra deficiency in humans argues in favor of a significant role of IL-36 in inflammatory skin diseases. 20,21 Recently, we have shown that dendritic cells (DCs) express IL-36R and that IL-36 stimulates the production of several cytokines and enhances the expression of costimulatory molecules in bone marrow-derived DCs (BMDCs). The stimulatory effects of IL-36 were more robust than those of the other members of the IL-1 family. In addition, IL-36 stimulated the production of interferon ␥ (IFN-␥), IL-4, and to a lesser extent IL-17 by cultured splenocytes and activated CD4 ϩ T cells, and IL-36 was able to act as an adjuvant to stimulate Th1 responses in vivo. 22 In the results described herein we show that, among CD4 ϩ T-cell subsets, IL-36R is predominantly expressed by naive CD4 ϩ T (referred to also as naive Th) cells and that IL-36 stimulates activated naive CD4 ϩ T (referred to also as Th0) cell ...

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Section: Il-36 and T-cell Responses 3485mentioning

confidence: 72%

IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

Vigne

Palmer

Martin

et al. 2012

Blood

Self Cite

191

190

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“…BCG-induced activation of macrophages has been associated with TNF production which is a critical cytokine in host defense mechanisms against mycobacterial infection [22]. Both BCG-infected and uninfected macrophages produce TNF although in lower amount than macrophages infected with virulent strains in which TNF supports mycobacterial growth [23].…”

Section: Introductionmentioning

confidence: 99%

Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability

Chávez‐Galán

Vesin

Martinvalet

et al. 2016

Journal of Immunology Research

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Mycobacterium bovis BCG, the current vaccine against tuberculosis, is ingested by macrophages promoting the development of effector functions including cell death and microbicidal mechanisms. Despite accumulating reports on M. tuberculosis, mechanisms of BCG/macrophage interaction remain relatively undefined. In vivo, few bacilli are sufficient to establish a mycobacterial infection; however, in vitro studies systematically use high mycobacterium doses. In this study, we analyze macrophage/BCG interactions and microenvironment upon infection with low BCG doses and propose an in vitro model to study cell activation without affecting viability. We show that RAW macrophages infected with BCG at MOI 1 activated higher and sustained levels of proinflammatory cytokines and transcription factors while MOI 0.1 was more efficient for early stimulation of IL-1β, MCP-1, and KC. Both BCG infection doses induced iNOS and NO in a dose-dependent manner and maintained nuclear and mitochondrial structures. Microenvironment generated by MOI 1 induced macrophage proliferation but not MOI 0.1 infection. In conclusion, BCG infection at low dose is an efficient in vitro model to study macrophage/BCG interactions that maintains macrophage viability and mitochondrial structures. This represents a novel model that can be applied to BCG research fields including mycobacterial infections, cancer immunotherapy, and prevention of autoimmunity and allergies.

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“…Granulomas are formed through cellular recruitment and are associated with production of cytokines and chemokines [15]. Among these cytokines, TNF and IFN-γ are the main players contributing to activation of macrophage host defense mechanisms [16]. Neutrophils are able to kill mycobacteria in vitro , but the in vivo relevance of neutrophils in the mycobacterial host defense remains a matter of debate [17].…”

Section: Introductionmentioning

confidence: 99%

Bacillus Calmette-Guerin Infection in NADPH Oxidase Deficiency: Defective Mycobacterial Sequestration and Granuloma Formation

et al. 2014

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Patients with chronic granulomatous disease (CGD) lack generation of reactive oxygen species (ROS) through the phagocyte NADPH oxidase NOX2. CGD is an immune deficiency that leads to frequent infections with certain pathogens; this is well documented for S. aureus and A. fumigatus, but less clear for mycobacteria. We therefore performed an extensive literature search which yielded 297 cases of CGD patients with mycobacterial infections; M. bovis BCG was most commonly described (74%). The relationship between NOX2 deficiency and BCG infection however has never been studied in a mouse model. We therefore investigated BCG infection in three different mouse models of CGD: Ncf1 mutants in two different genetic backgrounds and Cybb knock-out mice. In addition, we investigated a macrophage-specific rescue (transgenic expression of Ncf1 under the control of the CD68 promoter). Wild-type mice did not develop severe disease upon BCG injection. In contrast, all three types of CGD mice were highly susceptible to BCG, as witnessed by a severe weight loss, development of hemorrhagic pneumonia, and a high mortality (∼50%). Rescue of NOX2 activity in macrophages restored BCG resistance, similar as seen in wild-type mice. Granulomas from mycobacteria-infected wild-type mice generated ROS, while granulomas from CGD mice did not. Bacterial load in CGD mice was only moderately increased, suggesting that it was not crucial for the observed phenotype. CGD mice responded with massively enhanced cytokine release (TNF-α, IFN-γ, IL-17 and IL-12) early after BCG infection, which might account for severity of the disease. Finally, in wild-type mice, macrophages formed clusters and restricted mycobacteria to granulomas, while macrophages and mycobacteria were diffusely distributed in lung tissue from CGD mice. Our results demonstrate that lack of the NADPH oxidase leads to a markedly increased severity of BCG infection through mechanisms including increased cytokine production and impaired granuloma formation.

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Roles of Soluble and Membrane TNF and Related Ligands in Mycobacterial Infections: Effects of Selective and Non-selective TNF Inhibitors During Infection

Cited by 29 publications

References 91 publications

IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability

Bacillus Calmette-Guerin Infection in NADPH Oxidase Deficiency: Defective Mycobacterial Sequestration and Granuloma Formation

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