scholarly journals Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation

Blood ◽  
2020 ◽  
Vol 136 (19) ◽  
pp. 2162-2174 ◽  
Author(s):  
Paul Tsoukas ◽  
Emily Rapp ◽  
Lauren Van Der Kraak ◽  
Eric S. Weiss ◽  
Vinh Dang ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Inflammatory Responses ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Interleukin 18 ◽  
Promising Therapeutic Target ◽  
Life Threatening ◽  
Cd8 Depletion ◽  
Lcmv Infection

Abstract Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes typically associated with underlying hematologic and rheumatic diseases, respectively. Familial HLH is associated with genetic cytotoxic impairment and thereby to excessive antigen presentation. Extreme elevation of serum interleukin-18 (IL-18) has been observed specifically in patients with MAS, making it a promising therapeutic target, but how IL-18 promotes hyperinflammation remains unknown. In an adjuvant-induced MAS model, excess IL-18 promoted immunopathology, whereas perforin deficiency had no effect. To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with lymphocytic choriomeningitis virus (LCMV; strain Armstrong). LCMV infection is self-limited in wild-type mice, but Prf1−/− mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1−/− mice, albeit with minimal mortality. Like Prf1−/− mice, immunopathology was largely rescued by CD8 depletion or interferon-γ (IFNg) blockade. Unlike Prf1−/− mice, they showed normal target cell killing and normal clearance of viral RNA and antigens. Rather than impairing cytotoxicity, excess IL-18 acted on T lymphocytes to amplify their inflammatory responses. Surprisingly, combined perforin deficiency and transgenic IL-18 production caused spontaneous hyperinflammation specifically characterized by CD8 T-cell expansion and improved by IFNg blockade. Even Il18tg;Prf1-haplosufficient mice demonstrated hyperinflammatory features. Thus, excess IL-18 promotes hyperinflammation via an autoinflammatory mechanism distinct from, and synergistic with, cytotoxic impairment. These data establish IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation and support the rationale for an IL-18–driven subclass of hyperinflammation.

scholarly journals Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 595-603 ◽  
Author(s):  
Fernando E. Sepulveda ◽  
Franck Debeurme ◽  
Gaël Ménasché ◽  
Mathieu Kurowska ◽  
Marjorie Côte ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Late Onset ◽  
Lymphocytic Choriomeningitis ◽  
Immune Disorder ◽  
Genetic Abnormalities ◽  
Life Threatening ◽  
Syntaxin 11 ◽  
Lcmv Infection ◽  
Cytotoxic Effector

Abstract Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.

scholarly journals Virus-induced Transient Bone Marrow Aplasia: Major Role of Interferon-α/β during Acute Infection with the Noncytopathic Lymphocytic Choriomeningitis Virus

1997 ◽  
Vol 185 (3) ◽  
pp. 517-530 ◽  
Author(s):  
Daniel Binder ◽  
Jörg Fehr ◽  
Hans Hengartner ◽  
Rolf M. Zinkernagel
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Acute Infection ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Mouse Strains ◽  
Interferon Α ◽  
Wild Type ◽  
Ifn Γ ◽  
Lcmv Infection

The hematologic consequences of infection with the noncytopathic lymphocytic choriomeningitis virus (LCMV) were studied in wild-type mice with inherent variations in their interferon (IFN)-α/β responder ability and in mutant mice lacking α/β (IFN-α/β R0/0) or γ IFN (IFN-γ R0/0) receptors. During the first week of infection, wild type mice demonstrated a transient pancytopenia. Within a given genetic background, the extent of the blood cell abnormalities did not correlate with the virulence of the LCMV isolate but variations were detected between different mouse strains; they were found to depend on their IFN-α/β responder phenotype. Whereas IFN-γ R0/0 mice were comparable to wild-type mice, IFN-α/β R0/0 mice exhibited unchanged peripheral blood values during acute LCMV infection. In parallel, the bone marrow (BM) cellularity, the pluripotential and committed progenitor compartments were up to 30-fold reduced in wild type and IFN-γ R0/0, but remained unchanged in IFN-α/β R0/0 mice. Viral titers in BM 3 d after LCMV infection were similar in these mice, but antigen localization was different. Viral antigen was predominantly confined to stromal BM in normal mice and IFN-γ R0/0 knockouts, whereas, in IFN-α/β R0/0 mice, LCMV was detected in >90% of megakaryocytes and 10–15% of myeloid precursors, but not in erythroblasts. Although IFN-α/β efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-α/β R0/0 mice did not interfere with the number of circulating blood cells. Natural killer (NK) cell expansion and activity in the BM was comparable on day 3 after infection in mutant and control mice. Adaptive immune responses did not play a major role because comparable kinetics of LCMV-induced pancytopenia and transient depletion of the pluripotential and committed progenitor compartments were observed in CD80/0 and CD40/0 mice, in mice depleted of NK cells, in lpr mice, and in perforin-deficient (P0/0) mice lacking lytic NK cells. Thus, the reversible depression of hematopoiesis during early LCMV infection was not mediated by LCMV-WE–specific cytotoxic T lymphocyte, cytolysis, or secreted IFN-γ from virally induced NK cells but was a direct effect of IFN-α/β.

scholarly journals Coordinated Regulation and Widespread Cellular Expression of Interferon-Stimulated Genes (ISG) ISG-49, ISG-54, and ISG-56 in the Central Nervous System after Infection with Distinct Viruses

2006 ◽  
Vol 81 (2) ◽  
pp. 860-871 ◽  
Author(s):  
Christie Wacher ◽  
Marcus Müller ◽  
Markus J. Hofer ◽  
Daniel R. Getts ◽  
Regina Zabaras ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Dominant Role ◽  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Cellular Expression ◽  
The Central Nervous System ◽  
The Brain ◽  
Lcmv Infection

ABSTRACT The interferon (IFN)-stimulated genes (ISGs) ISG-49, ISG-54, and ISG-56 are highly responsive to viral infection, yet the regulation and function of these genes in vivo are unknown. We examined the simultaneous regulation of these ISGs in the brains of mice during infection with either lymphocytic choriomeningitis virus (LCMV) or West Nile virus (WNV). Expression of the ISG-49 and ISG-56 genes increased significantly during LCMV infection, being widespread and localized predominantly to common as well as distinct neuronal populations. Expression of the ISG-54 gene also increased but to lower levels and with a more restricted distribution. Although expression of the ISG-49, ISG-54, and ISG-56 genes was increased in the brains of LCMV-infected STAT1 and STAT2 knockout (KO) mice, this was blunted, delayed, and restricted to the choroid plexus, meninges, and endothelium. ISG-56 protein was regulated in parallel with the corresponding RNA transcript in the brain during LCMV infection in wild-type and STAT KO mice. Similar changes in ISG-49, ISG-54, and ISG-56 RNA levels and ISG-56 protein levels were observed in the brains of wild-type mice following infection with WNV. Thus, the ISG-49, ISG-54, and ISG-56 genes are coordinately upregulated in the brain during LCMV and WNV infection; this upregulation, in the case of LCMV, was totally (neurons) or partially (non-neurons) dependent on the IFN-signaling molecules STAT1 and STAT2. These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions.

scholarly journals Lymphocytic Choriomeningitis Virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses

2008 ◽  
Vol 194 (1-2) ◽  
pp. 70-82 ◽  
Author(s):  
Shenghua Zhou ◽  
Annett Halle ◽  
Evelyn A. Kurt-Jones ◽  
Anna M. Cerny ◽  
Ermelinda Porpiglia ◽  
...  
Keyword(s):  
Glial Cells ◽  
Inflammatory Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Lcmv Infection

scholarly journals Inducible nitric-oxide synthase plays a minimal role in lymphocytic choriomeningitis virus-induced, T cell-mediated protective immunity and immunopathology

1999 ◽  
Vol 80 (11) ◽  
pp. 2997-3005 ◽  
Author(s):  
C. Bartholdy ◽  
A. Nansen ◽  
J. Erbo Christensen ◽  
O. Marker ◽  
A. Randrup Thomsen
Keyword(s):  
Nitric Oxide ◽  
T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Cell Mediated Immune Response ◽  
Oxide Synthase ◽  
Deficient Mice ◽  
Lcmv Infection ◽  
Inducible Nitric Oxide

By using mice with a targetted disruption in the gene encoding inducible nitric-oxide synthase (iNOS), we have studied the role of nitric oxide (NO) in lymphocytic choriomeningitis virus (LCMV)-induced, T cell-mediated protective immunity and immunopathology. The afferent phase of the T cell-mediated immune response was found to be unaltered in iNOS-deficient mice compared with wild-type C57BL/6 mice, and LCMV- induced general immunosuppression was equally pronounced in both strains. In vivo analysis revealed identical kinetics of virus clearance, as well as unaltered clinical severity of systemic LCMV infection in both strains. Concerning the outcome of intracerebral infection, no significant differences were found between iNOS-deficient and wild-type mice in the number or composition of mononuclear cells found in the cerebrospinal fluid on day 6 post-infection. Likewise, NO did not influence the up-regulation of proinflammatory cytokine/chemokine genes significantly, nor did it influence the development of fatal meningitis. However, a reduced virus-specific delayed-type hypersensitivity reaction was observed in iNOS-deficient mice compared with both IFN-γ-deficient and wild-type mice. This might suggest a role of NO in regulating vascular reactivity in the context of T cell-mediated inflammation. In conclusion, these findings indicate a minimal role for iNOS/NO in the host response to LCMV. Except for a reduced local oedema in the knockout mice, iNOS/NO seems to be redundant in controlling both the afferent and efferent phases of the T cell-mediated immune response to LCMV infection.

scholarly journals Promotion of Alpha/Beta Interferon Induction during In Vivo Viral Infection through Alpha/Beta Interferon Receptor/STAT1 System-Dependent and -Independent Pathways

2002 ◽  
Vol 76 (9) ◽  
pp. 4520-4525 ◽  
Author(s):  
Lene Malmgaard ◽  
Thais P. Salazar-Mather ◽  
Casey A. Lewis ◽  
Christine A. Biron
Keyword(s):  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Beta Interferon ◽  
Interferon Induction ◽  
Elevated Expression ◽  
Alpha Beta ◽  
Β Receptor ◽  
Viral Components ◽  
Lcmv Infection

ABSTRACT Viruses and viral components can be potent inducers of alpha/beta interferons (IFN-α/β). In culture, IFN-α/β prime for their own expression, in response to viruses, through interferon regulatory factor 7 (IRF-7) induction. The studies presented here evaluated the requirements for functional IFN receptors and the IFN signaling molecule STAT1 in IFN-α/β induction during infections of mice with lymphocytic choriomeningitis virus (LCMV). At 24 h after infection, levels of induced IFN-α/β in serum were reduced 90 to 95% in IFN-α/β receptor-deficient (IFN-α/βR−/−) and STAT1−/− mice compared to those in wild-type mice. However, at 48 h, these mice showed elevated expression in the serum whereas IFN-α/β levels were still reduced >75% in IFN-α/βγR−/− mice even though the viral burden was heavy. Levels of IFN-β, IFN-α4, and non-IFN-α4 subtype mRNA expression correlated with IFN-α/β bioactivity, and all IFN-α/β subtypes were coincidentally detectable. IRF-7 mRNA was induced under conditions of IFN-α/β production, including late production in IFN-α/βR−/− mice. These data demonstrate that the presence of the virus alone is not sufficient to induce IFN-α/β during LCMV infection in vivo. Instead, autocrine amplification through the IFN-α/βR is necessary for optimal induction. In the absence of a functional IFN-α/βR, however, alternative mechanisms, independent of STAT1 but requiring a functional IFN-γR, take over.

scholarly journals Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate

2008 ◽  
Vol 417 (1) ◽  
pp. 223-238 ◽  
Author(s):  
Ana M. Ferreira ◽  
Mariana I. Ferrari ◽  
Andrés Trostchansky ◽  
Carlos Batthyany ◽  
José M. Souza ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Macrophage Activation ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inflammatory Stimuli ◽  
Anti Inflammatory ◽  
Electrophilic Reactivity

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPARγ (peroxisome-proliferator-activated receptor γ) ligand activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present study, we show increased nitration of cholesteryl-linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase ∼20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-γ; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the •NO (nitric oxide) inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPARγ and •NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-κB (nuclear factor κB) activation. Overall, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.

scholarly journals Interleukin-18 Expression after Focal Ischemia of the Rat Brain: Association with the Late-Stage Inflammatory Response

2002 ◽  
Vol 22 (1) ◽  
pp. 62-70 ◽  
Author(s):  
Sebastian Jander ◽  
Michael Schroeter ◽  
Guido Stoll
Keyword(s):  
Brain Ischemia ◽  
Late Stage ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Interferon Γ ◽  
Border Zone ◽  
Interleukin 1Β ◽  
Interleukin 18 ◽  
Caspase 1 ◽  
Focal Brain Ischemia

Interleukin-18, previously designated interferon γ-inducing factor, is a proinflammatory cytokine structurally related to interleukin-1β and is therefore considered a member of the growing family of interleukin-1–like cytokines. Both interleukin-18 and −1β are synthesized as inactive precursors that necessitate cleavage by caspase-1 for functional activity. In this study, the authors analyzed the expression pattern of interleukin-18, −1β, and caspase-1 in focal brain ischemia induced in rats either by permanent middle cerebral artery occlusion or by photothrombosis of cortical microvessels. Using reverse transcriptase-polymerase chain reaction, they found a delayed increase of interleukin-18 mRNA starting at 48 hours and reaching its peak between 7 and 14 days after ischemia. In contrast, interleukin-1β mRNA peaked within 16 hours and was downregulated thereafter. The time course of caspase-1 mRNA expression paralleled that of interleukin-18, but not of interleukin-1β mRNA. Immunocytochemically, interleukin-18 expression was localized to ED1-positive phagocytic microglia/macrophages infiltrating the necrotic lesion between 3 and 6 days after ischemia. In contrast, interleukin-1β immunoreactivity was expressed by ramified microglia in the infarct border zone and remote ipsilateral cortex during the first 16 hours postlesion. Induction of interleukin-18 was not accompanied by detectable expression of interferon-γ mRNA. Their data show spatial and temporal diversity in interleukin-1 and −18 cytokine family expression in brain ischemia, and suggest a role of the interleukin-18/caspase-1 pathway in late-stage inflammatory responses to focal brain ischemia.

scholarly journals Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression.

1991 ◽  
Vol 174 (6) ◽  
pp. 1425-1429 ◽  
Author(s):  
W P Fung-Leung ◽  
T M Kündig ◽  
R M Zinkernagel ◽  
T W Mak
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Mutant Mice ◽  
Cd4 T Cell ◽  
Wild Type ◽  
Lcmv Infection

The immune response against lymphocytic choriomeningitis virus (LCMV) was studied in a mutant mouse strain that does not possess CD8+ T lymphocytes. Virus-specific cytotoxic T cell activity was generated in spleens of wild-type mice in an acute LCMV infection but was not measurable in mutant mice. Injection of replicating LCMV into footpads of wild-type mice induced a CD8+ T cell-mediated swelling that peaked on day 8, followed by a CD4+ T cell-mediated swelling that peaked on day 11, whereas mutant mice exhibited only the CD4+ T cell-mediated swelling. After intracerebral inoculation with LCMV-Armstrong, all wild-type mice died of classical CD8+ T cell-dependent choriomeningitis in 8-10 days. Mutant mice showed symptoms of general malaise but most of them survived. Mutant mice depleted of CD4+ T cells by monoclonal antibody treatment showed no clinical signs of sickness. On day 9 after intravenous infection with LCMV-WE, virus was detected at high titers in spleens and livers of mutant mice but not in those of wild-type mice. On day 70 after injection of LCMV-WE into footpads, virus was not detected in wild-type mice and in one of the three mutant mice tested, but was still measurable in kidneys of the other two mutant mice. These results confirm in a new animal model that CD8+ T cell-mediated immunity is crucial in LCMV clearance and in the immunopathological disease during LCMV infection. In addition, our results demonstrated a less severe form of choriomeningitis mediated by CD4+ T cells and slow clearance of LCMV by alternative pathways independent of CD8+ T cells.

scholarly journals Adiponectin Deficiency Does Not Affect the Inflammatory Response to Endotoxin or Concanavalin A in Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5019-5022 ◽  
Author(s):  
Maria Pini ◽  
Joseph A. Sennello ◽  
Lawrence Chan ◽  
Giamila Fantuzzi
Keyword(s):  
Inflammatory Response ◽  
Concanavalin A ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Body Weight Loss ◽  
Interferon Γ ◽  
Experimental Models ◽  
High Dose ◽  
Wild Type

Adiponectin (APN) is an adipocyte-derived protein that regulates insulin sensitivity and displays antiinflammatory activities in a variety of experimental models. The present study aimed at investigating the effect of APN deficiency on the inflammatory response to endotoxin (lipopolysaccharide, LPS) and Concanavalin A (ConA) in vivo in mice. Administration of a high dose of LPS (100 μg/mouse) induced production of comparable amounts of IL-6, TNFα, and interferon-γ in wild-type (WT) and APN knockout (KO) mice. Furthermore, LPS-induced hypoglycemia, anorexia, and body weight loss did not differ between WT and APN KO mice. Administration of a low dose of LPS (100 or 10 ng/g) in association with d-galactosamine induced equivalent mortality rates, hepatotoxicity, and serum IL-6 in WT and APN KO mice. Finally, ConA-induced cytokine production and hepatotoxicity were not significantly different between WT and APN KO mice. These data indicate that—despite its well-described role as an antiinflammatory molecule—endogenous APN does not play a critical role in modulating the inflammatory responses to LPS and ConA in mice.

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