Faculty Opinions recommendation of Type I interferon inhibits interleukin-1 production and inflammasome activation.

Francisella tularensis is a pathogenic bacterium whose virulence is linked to its ability to replicate within the host cell cytosol. Entry into the macrophage cytosol activates a host-protective multimolecular complex called the inflammasome to release the proinflammatory cytokines interleukin (IL)-1β and -18 and trigger caspase-1–dependent cell death. In this study, we show that cytosolic F. tularensis subspecies novicida (F. novicida) induces a type I interferon (IFN) response that is essential for caspase-1 activation, inflammasome-mediated cell death, and release of IL-1β and -18. Extensive type I IFN–dependent cell death resulting in macrophage depletion occurs in vivo during F. novicida infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria monocytogenes but not vacuole-localized Salmonella enterica serovar Typhimurium or extracellular adenosine triphosphate. These results show the specific connection between type I IFN signaling and inflammasome activation, which are two sequential events triggered by the recognition of cytosolic bacteria. To our knowledge, this is the first example of the positive regulation of inflammasome activation. This connection underscores the importance of the cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses.

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Type I Interferon and Interleukin-1 Driven Inflammatory Pathways as Targets for HDT in Tuberculosis

Advances in Host-Directed Therapies Against Tuberculosis ◽

10.1007/978-3-030-56905-1_14 ◽

2020 ◽

pp. 219-232

Author(s):

Katrin D. Mayer-Barber ◽

Christopher M. Sassetti

Keyword(s):

Type I Interferon ◽

Interleukin 1 ◽

Type I ◽

Inflammatory Pathways

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Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling

Biochemical Society Transactions ◽

10.1042/bst20160259 ◽

2017 ◽

Vol 45 (4) ◽

pp. 929-935 ◽

Cited By ~ 9

Author(s):

Kenji Funami ◽

Misako Matsumoto ◽

Hiroyuki Oshiumi ◽

Fuyuhiko Inagaki ◽

Tsukasa Seya

Keyword(s):

Amino Acids ◽

Type I Interferon ◽

Structural Information ◽

Interleukin 1 ◽

Endotoxin Shock ◽

Type I Interferons ◽

Type I ◽

Tir Domain ◽

Adaptor Molecule ◽

Acidic Amino Acids

Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS), produces pro-inflammatory cytokines and type I interferons, and associates with a trigger of endotoxin shock. TLR4 is interacted with a TIR domain-containing adaptor molecule-2 (TICAM-2)/TRAM [TRIF (TIR domain-containing adaptor-inducing interferon-β)-related adaptor molecule] via its Toll–interleukin-1 receptor homology (TIR) domain. TICAM-2 acts as a scaffold protein and activates TIR domain-containing adaptor molecule-1 (TICAM-1)/TRIF. According to the structural analysis by NMR, TICAM-2 interacts with TICAM-1 by the acidic amino acids motif, E87/D88/D89. The TIR domain of TICAM-2 couples with the dimer of TIR domain of TLR4 beneath the membrane, and TICAM-2 itself also forms dimer and constitutes a binding site with TICAM-1. Endosomal localization of TICAM-2 is essential for TLR4-mediated type I interferon-inducing signal from the endosome. N-terminal myristoylation allows TICAM-2 to anchor to the endosomal membrane. Additionally, we have identified two acidic amino acids, D91/E92, as a functional motif that cooperatively determines endosomal localization of TICAM-2. This structural information of TICAM-2 suggests that the specific structure is indispensable for the endosomal localization and type I interferon production of TICAM-2. Taken together with the knowledge on cytoplasmic sensors for LPS, TICAM-2/TICAM-1 may conform to a signal network on TLR4 to facilitate induction of cytokine disorders.

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25-Hydroxycholesterol suppresses interleukin-1–driven inflammation downstream of type I interferon

Science ◽

10.1126/science.1254790 ◽

2014 ◽

Vol 345 (6197) ◽

pp. 679-684 ◽

Cited By ~ 217

Author(s):

Andrea Reboldi ◽

Eric V. Dang ◽

Jeffrey G. McDonald ◽

Guosheng Liang ◽

David W. Russell ◽

...

Keyword(s):

Type I Interferon ◽

Interleukin 1 ◽

Type I ◽

Autoimmune Encephalomyelitis ◽

Mouse Macrophages ◽

Element Binding Protein ◽

Increased Sensitivity ◽

Feedback Pathway ◽

Inflammasome Activity ◽

Experimental Autoimmune

Type I interferon (IFN) protects against viruses, yet it also has a poorly understood suppressive influence on inflammation. Here, we report that activated mouse macrophages lacking the IFN-stimulated gene cholesterol 25-hydroxylase (Ch25h) and that are unable to produce the oxysterol 25-hydroxycholesterol (25-HC) overproduce inflammatory interleukin-1 (IL-1) family cytokines. 25-HC acts by antagonizing sterol response element–binding protein (SREBP) processing to reduce Il1b transcription and to broadly repress IL-1–activating inflammasomes. In accord with these dual actions of 25-HC, Ch25h-deficient mice exhibit increased sensitivity to septic shock, exacerbated experimental autoimmune encephalomyelitis, and a stronger ability to repress bacterial growth. These findings identify an oxysterol, 25-HC, as a critical mediator in the negative-feedback pathway of IFN signaling on IL-1 family cytokine production and inflammasome activity.

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