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Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner

Overview of attention for article published in Arthritis Research & Therapy, October 2015
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2 tweeters

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Title
Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner
Published in
Arthritis Research & Therapy, October 2015
DOI 10.1186/s13075-015-0794-z
Pubmed ID
Authors

Carla M. Cuda, Alexander V. Misharin, Sonal Khare, Rana Saber, FuNien Tsai, Amy M. Archer, Philip J. Homan, G. Kenneth Haines, Jack Hutcheson, Andrea Dorfleutner, G. R. Scott Budinger, Christian Stehlik, Harris Perlman

Abstract

Although 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. Cre (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. Loss 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. These data demonstrate that caspase-8 functions uniquely in macrophages by controlling the response to TLR activation and macrophage polarization in an RIPK-dependent manner.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 44 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Norway 1 2%
Unknown 43 98%

Demographic breakdown

Readers by professional status Count As %
Researcher 8 18%
Student > Bachelor 7 16%
Student > Ph. D. Student 6 14%
Student > Master 5 11%
Student > Doctoral Student 4 9%
Other 4 9%
Unknown 10 23%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 10 23%
Agricultural and Biological Sciences 7 16%
Medicine and Dentistry 6 14%
Immunology and Microbiology 5 11%
Environmental Science 1 2%
Other 3 7%
Unknown 12 27%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 12 July 2016.
All research outputs
#9,566,799
of 12,451,992 outputs
Outputs from Arthritis Research & Therapy
#1,652
of 1,983 outputs
Outputs of similar age
#172,358
of 273,546 outputs
Outputs of similar age from Arthritis Research & Therapy
#200
of 254 outputs
Altmetric has tracked 12,451,992 research outputs across all sources so far. This one is in the 19th percentile – i.e., 19% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,983 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.0. This one is in the 16th percentile – i.e., 16% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 273,546 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 30th percentile – i.e., 30% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 254 others from the same source and published within six weeks on either side of this one. This one is in the 17th percentile – i.e., 17% of its contemporaries scored the same or lower than it.