scholarly journals Tumor Necrosis Factor-Mediated Survival of CD169 + Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection

2017 ◽  
Vol 92 (3) ◽  
Author(s):  
Prashant V. Shinde ◽  
Haifeng C. Xu ◽  
Sathish Kumar Maney ◽  
Andreas Kloetgen ◽  
Sukumar Namineni ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Virus Infection ◽  
Vesicular Stomatitis Virus ◽  
Virus Replication ◽  
Immune Activation ◽  
Tumor Necrosis ◽  
Severe Disease ◽  
Innate Immune ◽  
Vesicular Stomatitis ◽  
Necrosis Factor

ABSTRACT Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169 + cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169 + cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b + Ly6C + Ly6G + cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169 + cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169 + cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169 + cells and innate and adaptive immune activation during VSV infection. IMPORTANCE Over the last decade, strategically placed CD169 + metallophilic macrophages in the marginal zone of the murine spleen and lymph nodes (LN) have been shown to play a very important role in host defense against viral pathogens. CD169 + macrophages have been shown to activate innate and adaptive immunity via “enforced virus replication,” a controlled amplification of virus particles. However, the factors regulating the CD169 + macrophages remain to be studied. In this paper, we show that after vesicular stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF), which signals via TNFR1, and promote enforced virus replication in CD169 + macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance.

scholarly journals Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells

2008 ◽  
Vol 82 (16) ◽  
pp. 7790-7798 ◽  
Author(s):  
Marlynne Q. Nicol ◽  
Jean-Marie Mathys ◽  
Albertina Pereira ◽  
Kevin Ollington ◽  
Michael H. Ieong ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Innate Immune ◽  
Hiv Positive ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Immunodeficiency Virus ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-α) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-α activity, as measured by the TNF-α/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-α is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-α production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-α in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-α production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

Tumor Necrosis Factor–α Promoter −308/238 Polymorphism Association with Less Severe Disease in Ankylosing Spondylitis is Unrelated to Serum TNF-α and Does Not Predict TNF Inhibitor Response

2014 ◽  
Vol 41 (8) ◽  
pp. 1675-1682 ◽  
Author(s):  
Johannes C. Nossent ◽  
Sylvia Sagen-Johnsen ◽  
Gunnstein Bakland
Keyword(s):  
Ankylosing Spondylitis ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Age Of Onset ◽  
Severe Disease ◽  
Sandwich Elisa ◽  
Tnf Inhibitor ◽  
Cross Sectional ◽  
Tnf Α ◽  
Necrosis Factor

Objective.Despite the clinical efficacy of tumor necrosis factor inhibitors (TNFi), the manner in which TNF-α contributes to disease in patients with ankylosing spondylitis (AS) remains unresolved. We investigated the relationship between TNF-α gene promoter region polymorphism, serum TNF-α levels, and clinical phenotype.Methods.We did a cross-sectional and longitudinal cohort study in TNFi-naive patients with AS (n = 335). Clinical data and biological samples were collected during a research visit with genotyping for TNF-α −238 A/G and −308 A/G performed by Taqman RT-PCR and TNF levels determined by sandwich ELISA. Longitudinal TNF levels were monitored in unselected patients (n = 61).Results.TNF-α −308 GA/AA genotype was present in 14% and TNF-α −238 GA/AA genotype in 1% of patients. TNF-α −308 GA/AA genotype was associated with a reduced risk of uveitis and better spinal function, while TNF-α −238 GA/AA genotype was associated with later age of onset and lower erythrocyte sedimentation rate (ESR). Serum TNF-α level was lower in patients with AS (151 pg/ml) than in controls (263 pg/ml), because more patients with AS had undetectable serum TNF-α (66 vs 25%, p < 0.001). TNFi treatment did not influence serum TNF-α. There was no effect of TNF-α −308/−238 or HLA-B27 genotype on serum TNF-α or subsequent initiation of TNFi.Conclusion.TNF-α −238 or −308 GA/AA genotypes in patients with AS are associated with signs of less severe disease. Serum TNF-α is, however, undetectable in two-thirds of patients with AS and is not influenced by TNF-α promoter genotype or TNFi therapy. These data suggest a more significant role for TNF-α at local sites of inflammation in AS than through systemic effects.

scholarly journals Tumor Necrosis Factor (TNF) Receptor Shedding Controls Thresholds of Innate Immune Activation That Balance Opposing TNF Functions in Infectious and Inflammatory Diseases

2004 ◽  
Vol 200 (3) ◽  
pp. 367-376 ◽  
Author(s):  
Sofia Xanthoulea ◽  
Manolis Pasparakis ◽  
Stavroula Kousteni ◽  
Cord Brakebusch ◽  
David Wallach ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Bacterial Infections ◽  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
Endotoxic Shock ◽  
Innate Immune ◽  
Disease Assessment ◽  
Recurrent Fever ◽  
Receptor Shedding ◽  
Necrosis Factor

Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor–dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.

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