TNFRp55 modulates IL-6 and nitric oxide responses following Yersinia lipopolysaccharide stimulation in peritoneal macrophages

Eliçabe, Ricardo Javier; Arias, José L.; Rabinovich, Gabriel A.; Genaro, María Silvia Di

doi:10.1016/j.imbio.2011.05.009

Cited by 9 publications

(8 citation statements)

References 44 publications

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“…These data are in agreement with previous findings on the ability of exogenous Gal-1 to skew the balance from classically activated M1 macrophages/ microglia toward an alternatively activated M2 phenotype (30,32). These results are relevant in the context of Yersinia infection because Y. enterocolitica and Y. pseudotuberculosis control NO production in murine macrophages, with YopJ, YopE, and YopH being responsible for such effects (8,73,74). In this regard, although Y. enterocolitica can trigger apoptosis of infected macrophages (11,12,15,16), Gal-1 did not seem to mediate this effect (Fig.…”

Section: Discussionsupporting

confidence: 93%

“…However, recent studies in a setting of osteoarthritis demonstrated that exogenous Gal-1 could also activate an NF-kBregulated gene network in chondrocytes (76), suggesting that this lectin may differentially control pro-or anti-inflammatory gene expression in different cell types and physiologic/pathologic settings. In this context, recent studies suggested that TNFR p55 acts as a regulatory switch that limits Y. enterocolitica-induced reactive arthritis by modulating IL-6, NO, and NF-kB pathways and controlling Treg expansion (5,8,77). Because these molecular and cellular pathways are preferred targets of the immunoregulatory activity of Gal-1, a possible cross-talk between TNFR p55 signaling and this endogenous lectin might contribute to hierarchically dissect the immunopathogenesis of Y. enterocolitica infection and the underlying tissue damage.…”

Section: Discussionmentioning

confidence: 99%

“…During the course of infection, Y. enterocolitica reaches the intestinal tract, invades M cells of Peyer's patches (PPs), and disseminates to the mesenteric lymph nodes (MLNs), spleen, and liver (1). Although innate immune cells, including NK cells, dendritic cells (DCs), and macrophages, confer early protection during the course of Y. enterocolitica infection, Th1 and Th17 effector cells ultimately provide antibacterial immunity depending on the magnitude of the inoculum, entry route, and engagement of selected pattern recognition receptors (2)(3)(4)(5)(6)(7)(8). However, despite activation of a broad spectrum of immune-protective mechanisms, Y. enterocolitica has evolved a complex machinery to subvert antibacterial responses (9).…”

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confidence: 99%

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Galectin-1–Driven Tolerogenic Programs Aggravate Yersinia enterocolitica Infection by Repressing Antibacterial Immunity

Davicino

Méndez-Huergo

Eliçabe

et al. 2017

The Journal of Immunology

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is an enteropathogenic bacterium that causes gastrointestinal disorders, as well as extraintestinal manifestations. To subvert the host's immune response, uses a type III secretion system consisting of an injectisome and effector proteins, called outer proteins (Yops), that modulate activation, signaling, and survival of immune cells. In this article, we show that galectin-1 (Gal-1), an immunoregulatory lectin widely expressed in mucosal tissues, contributes to pathogenicity by undermining protective antibacterial responses. We found higher expression of Gal-1 in the spleen and Peyer's patches of mice infected orogastrically with serotype O:8 compared with noninfected hosts. This effect was prevented when mice were infected with lacking YopP or YopH, two critical effectors involved in bacterial immune evasion. Consistent with a regulatory role for this lectin during pathogenesis, mice lacking Gal-1 showed increased weight and survival, lower bacterial load, and attenuated intestinal pathology compared with wild-type mice. These protective effects involved modulation of NF-κB activation, TNF production, and NO synthesis in mucosal tissue and macrophages, as well as systemic dysregulation of IL-17 and IFN-γ responses. In vivo neutralization of these proinflammatory cytokines impaired bacterial clearance and eliminated host protection conferred by Gal-1 deficiency. Finally, supplementation of recombinant Gal-1 in mice lacking Gal-1 or treatment of wild-type mice with a neutralizing anti-Gal-1 mAb confirmed the immune inhibitory role of this endogenous lectin during infection. Thus, targeting Gal-1-glycan interactions may contribute to reinforce antibacterial responses by reprogramming innate and adaptive immune mechanisms.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Galectin-1–Driven Tolerogenic Programs Aggravate Yersinia enterocolitica Infection by Repressing Antibacterial Immunity

Davicino

Méndez-Huergo

Eliçabe

et al. 2017

The Journal of Immunology

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“…Future studies are being conducted to elucidate the link between altered T reg cell frequency and IL‐10 production in TNFRp55‐deficient mice. On the other hand, we have recently demonstrated that TNFRp55 signaling modulates macrophage functions in response to Yersinia lipopolyssacharide stimulation 21 . Since T eff and T reg cell subsets do not express TNFRp55, 8 this signaling effect may negatively regulate the inflammatory response of non‐lymphoid cells through differential modulation of anti‐inflammatory or pro‐inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

TNFRp55 controls regulatory T cell responses in Yersinia‐induced reactive arthritis

et al. 2012

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In addition to its well-known pro-inflammatory effects, tumor necrosis factor (TNF) displays anti-inflammatory activities through mechanisms poorly understood. Previously, we reported the development of severe chronic Yersinia enterocolitica-induced reactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. As regulatory T (T(reg)) cells limit chronic inflammation, here we aim to investigate the expansion and function of CD4(+)CD25(+)FoxP3(+) T(reg) cells in the ReA animal model. The number of T(reg) cells as well as the FoxP3 mRNA expression and interleukin (IL)-10 levels were significantly decreased in joint regional lymph nodes (RLNs) of TNFRp55(-/-) mice vs wild-type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, the number of T(reg) cell in TNFRp55(-/-) was similar to WT mice. To explore the in vivo function of T(reg) cells at this chronic phase in WT and TNFRp55-deficient mice, we adoptively transferred CD4(+) T cells from TNFRp55-deficient mice of day 21, into naïve WT or TNFRp55(-/-) mice. When knockout mice were used as recipients we observed higher delayed-type hypersensitivity (DTH) responses and joint inflammation after heat-killed Yersinia (HKY) stimulation. Accordingly, we found higher levels of IL-17, interferon (IFN)-γ, IL-6, transforming growth factor (TGF)-β1 and IL-12/23p40 and lower IL-10 levels in RLN of paws challenged with HKY in TNFRp55(-/-) recipient mice. In addition, we found that CD4(+) T cells from TNFRp55(-/-) mice controlled antigen-specific IL-12/23(p40) production in recipient WT mice. Our results show that TNFRp55 controls the induction and function of T(reg) cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.

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“…Our findings in Yersinia-induced ReA in TNFRp55 −/− mice demonstrated that, in the absence of TNF signaling, redundant pathways, particularly Th17 and Th1 effector cells, may act in concert to sustain inflammation in bacterial induced ReA [68]. Recently, we reported that TNFRp55 modulates macrophage functions in response to Yersinia LPS stimulation suggesting an essential regulatory role of TNF via TNFRp55 signaling [93]. Furthermore, we have reported that this pathway controlled the induction and function of Treg cells through differential regulation of cytokine production [69].…”

Section: Treatmentmentioning

confidence: 55%

Reactive Arthritis: From Clinical Features to Pathogenesis

Cargnelutti¹,

Genaro²

2013

IJCM

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Reactive arthritis (ReA) is a sterile synovitis which occurs after a gastrointestinal or urogenital infection. ReA belongs to Spondyloarthritis (SpA), a group of diseases that share several clinical and radiological features including familiar clustering, absence of rheumatoid factor and association with HLA-B27. Clinically, ReA is characterized by an asymmetric arthritis predominantly affecting the lower limbs, often associated with urethritis, conjunctivitis and other extraarticular symptoms. The ReA prevalence depends on the incidence of causative pathogens. The ReA diagnosis is based on clinical features and serological tests to evidence previous infection. Different treatment including antibiotics, disease modifying antirheumatic drugs (DMARs) and biologic agents has been recommended. Even though knowing that infections trigger the joint inflammation, the ReA pathogenesis remains to be poorly understood. Several animal models and in vitro studies have been used to elucidate the mechanisms involved in ReA development. In this sense, HLA-B27 transgenic rat or mice have been used to explain the role of this molecule in SpA aetiopathogenesis. Moreover, the infectious model of Yersinia-induced ReA in rodents has shed some lights on the relationship between host genetic susceptibility to infection and abnormal immune response in ReA development. Understanding the immune mediators triggering ReA will contribute to find a specific treatment for this arthritis. In this review, we focus on clinical features, epidemiology, treatment, and the different attempts to understand the pathogenesis of ReA.

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TNFRp55 modulates IL-6 and nitric oxide responses following Yersinia lipopolysaccharide stimulation in peritoneal macrophages

Cited by 9 publications

References 44 publications

Galectin-1–Driven Tolerogenic Programs Aggravate Yersinia enterocolitica Infection by Repressing Antibacterial Immunity

Galectin-1–Driven Tolerogenic Programs Aggravate Yersinia enterocolitica Infection by Repressing Antibacterial Immunity

TNFRp55 controls regulatory T cell responses in Yersinia‐induced reactive arthritis

Reactive Arthritis: From Clinical Features to Pathogenesis

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