Faculty Opinions recommendation of Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases.

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

Journal of Virology ◽

10.1128/jvi.01637-17 ◽

2017 ◽

Vol 92 (3) ◽

Cited By ~ 4

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.

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Histamine Antagonizes Tumor Necrosis Factor (TNF) Signaling by Stimulating TNF Receptor Shedding from the Cell Surface and Golgi Storage Pool

Journal of Biological Chemistry ◽

10.1074/jbc.m212662200 ◽

2003 ◽

Vol 278 (24) ◽

pp. 21751-21760 ◽

Cited By ~ 60

Author(s):

Jun Wang ◽

Rafia S. Al-Lamki ◽

Hui Zhang ◽

Nancy Kirkiles-Smith ◽

Mary Lou Gaeta ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Cell Surface ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Storage Pool ◽

Receptor Shedding ◽

Necrosis Factor

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The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

Molecular and Cellular Biology ◽

10.1128/mcb.21.12.3986-3994.2001 ◽

2001 ◽

Vol 21 (12) ◽

pp. 3986-3994 ◽

Cited By ~ 100

Author(s):

Anne Devin ◽

Yong Lin ◽

Shoji Yamaoka ◽

Zhiwei Li ◽

Michael Karin ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Leucine Zipper ◽

Nuclear Translocation ◽

Ring Finger ◽

Tnf Receptor ◽

Death Domain ◽

Iκb Kinase ◽

Cytokine Tumor Necrosis Factor ◽

Necrosis Factor

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

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Membrane lymphotoxin-α2β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist

Cell Death and Disease ◽

10.1038/s41419-021-03633-8 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Kirstin Kucka ◽

Isabell Lang ◽

Tengyu Zhang ◽

Daniela Siegmund ◽

Juliane Medler ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Asymmetric Structure ◽

Tnf Receptor ◽

Membrane Bound ◽

Necrosis Factor

AbstractIn the early 1990s, it has been described that LTα and LTβ form LTα2β and LTαβ2 heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ2–LTβR system has been intensively studied while the LTα2β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα2β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα2β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα2β (memLTα2β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα2β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.

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

Journal of Virology ◽

10.1128/jvi.00362-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 7790-7798 ◽

Cited By ~ 26

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.

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