ArticleBlood2020
Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation.
Article in Blood, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 40 citations in OpenAlex.
- Mycobacterial Immune Reconstitution Inflammatory Syndrome in HIV is Associated With Protein-Altering Variants in Hemophagocytic Lymphohistiocytosis-Related Genes.The Journal of infectious diseases · 2023Trial
- Low Peripheral Blood Counts and Elevated Proinflammatory Cytokines Signal a Poor CD19 Chimeric Antigen Receptor T-cell Response in Acute Lymphoblastic Leukemia.Transplantation and cellular therapy · 2025Article
- Article
- Role of DOCK8 in cytokine storm syndromes.The Journal of allergy and clinical immunology · 2025Article
- Weal and woe of interleukin-18 in the T cell therapy of cancer.Journal for immunotherapy of cancer · 2025Review
- NLRP3 Inflammasome Triggers Inflammation of Obstructive Sleep Apnea.Current molecular medicine · 2025Review
- The 4Pediatric rheumatology online journal · 2024Article
- Murine Models of Familial Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- Heterogeneity of macrophage activation syndrome and treatment progression.Frontiers in immunology · 2024Review
- Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.Advances in experimental medicine and biology · 2024Review
- Cytokines in Cytokine Storm Syndrome.Advances in experimental medicine and biology · 2024Review
- Cytokine Storm Syndrome Associated with Systemic Juvenile Idiopathic Arthritis.Advances in experimental medicine and biology · 2024Review
- Autoinflammatory Contributors to Cytokine Storm.Advances in experimental medicine and biology · 2024Review
- Kawasaki Disease-Associated Cytokine Storm Syndrome.Advances in experimental medicine and biology · 2024Review
- Murine Models of Secondary Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- Biological and clinical roles of IL-18 in inflammatory diseases.Nature reviews. Rheumatology · 2024Review
- Type 1 Interferon-Stimulated Gene Expression and Disease Activity in Pediatric Rheumatic Diseases: No Composite Scores Needed?ACR open rheumatology · 2023Article
- Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation.Blood advances · 2023Article
- The Multifaceted Immunology of Cytokine Storm Syndrome.Journal of immunology (Baltimore, Md. : 1950) · 2023Review
- Bidirectional two-sample Mendelian randomization analysis reveals a causal effect of interleukin-18 levels on postherpetic neuralgia risk.Frontiers in immunology · 2023Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.