ArticleArthritis research & therapy2015
Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner.
Article in Arthritis research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 39 citations in OpenAlex.
- Article
- A Novel Cause of CIDP: Homozygous Hotspot Mutation, c.793 C > T in CASP8 Gene.Journal of clinical immunology · 2025Review
- Comprehensive analysis of myeloid reporter mice.bioRxiv : the preprint server for biology · 2025Article
- Exploring caspase functions in mouse models.Apoptosis : an international journal on programmed cell death · 2024Review
- Caspase 8 deletion causes infection/inflammation-induced bone marrow failure and MDS-like disease in mice.Cell death & disease · 2024Article
- Targeting caspase-8: a new strategy for combating hepatocellular carcinoma.Frontiers in immunology · 2024Review
- Apoptotic cell death in disease-Current understanding of the NCCD 2023.Cell death and differentiation · 2023Review
- Activation of necroptosis pathway in podocyte contributes to the pathogenesis of focal segmental glomerular sclerosis.Clinical and experimental nephrology · 2022Article
- Targeting RIP Kinases in Chronic Inflammatory Disease.Biomolecules · 2021Review
- The role of caspase-8 in the tumor microenvironment of ovarian cancer.Cancer metastasis reviews · 2021Review
- Multiple roles of caspase-8 in cell death, inflammation, and innate immunity.Journal of leukocyte biology · 2021Review
- Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD.Life science alliance · 2020Article
- ASEP: Gene-based detection of allele-specific expression across individuals in a population by RNA sequencing.PLoS genetics · 2020Article
- Senescence in Pulmonary Fibrosis: Between Aging and Exposure.Frontiers in medicine · 2020Review
- RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Early Protection by Resveratrol in Rat Lung Transplantation.Medical science monitor : international medical journal of experimental and clinical research · 2019Article
- Remarkably Robust Antiviral Immune Response despite Combined Deficiency in Caspase-8 and RIPK3.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- The Effects of Dendritic Cell Hypersensitivity on Persistent Viral Infection.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- Bim suppresses the development of SLE by limiting myeloid inflammatory responses.The Journal of experimental medicine · 2017Article
- The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis.Clinical immunology (Orlando, Fla.) · 2017Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
introductionAlthough caspase-8 is a well-established initiator of apoptosis and suppressor of necroptosis, recent evidence suggests that this enzyme maintains functions beyond its role in cell death. As cells of the innate immune system, and in particular macrophages, are now at the forefront of autoimmune disease pathogenesis, we examined the potential involvement of caspase-8 within this population.
methodsCre (LysM) Casp8 (fl/fl) mice were bred via a cross between Casp8 (fl/fl) mice and Cre (LysM) mice, and RIPK3 (-/-) Cre (LysM) Casp8 (fl/fl) mice were generated to assess the contribution of receptor-interacting serine-threonine kinase (RIPK)3. Immunohistochemical and immunofluorescence analyses were used to examine renal damage. Flow cytometric analysis was employed to characterize splenocyte distribution and activation. Cre (LysM) Casp8 (fl/fl) mice were treated with either Toll-like receptor (TLR) agonists or oral antibiotics to assess their response to TLR activation or TLR agonist removal. Luminex-based assays and enzyme-linked immunosorbent assays were used to measure cytokine/chemokine and immunoglobulin levels in serum and cytokine levels in cell culture studies. In vitro cell culture was used to assess macrophage response to cell death stimuli, TLR activation, and M1/M2 polarization. Data were compared using the Mann-Whitney U test.
resultsLoss of caspase-8 expression in macrophages promotes onset of a mild systemic inflammatory disease, which is preventable by the deletion of RIPK3. In vitro cell culture studies reveal that caspase-8-deficient macrophages are prone to a caspase-independent death in response to death receptor ligation; yet, caspase-8-deficient macrophages are not predisposed to unchecked survival, as analysis of mixed bone marrow chimeric mice demonstrates that caspase-8 deficiency does not confer preferential expansion of myeloid populations. Loss of caspase-8 in macrophages dictates the response to TLR activation, as injection of TLR ligands upregulates expression of costimulatory CD86 on the Ly6C(high)CD11b(+)F4/80(+) splenic cells, and oral antibiotic treatment to remove microbiota prevents splenomegaly and lymphadenopathy in Cre (LysM) Casp8 (fl/fl) mice. Further, caspase-8-deficient macrophages are hyperresponsive to TLR activation and exhibit aberrant M1 macrophage polarization due to RIPK activity.
conclusionsThese data demonstrate that caspase-8 functions uniquely in macrophages by controlling the response to TLR activation and macrophage polarization in an RIPK-dependent manner.
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