Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study

Abstract

BackgroundCaspase-1 is present in the cytosol as an inactive zymogen and requires the protein complexes named “inflammasomes” for proteolytic activation. However, it remains unclear whether the proteolytic activity of caspase-1 is confined only to the cytosol where inflammasomes are assembled to convert inactive pro-caspase-1 to active caspase-1.MethodsWe conducted meticulous data analysis methods on proteomic, protein interaction, protein intracellular localization, and gene expressions of 114 experimentally identified caspase-1 substrates and 38 caspase-1 interaction proteins in normal physiological conditions and in various pathologies.ResultsWe made the following important findings: (1) Caspase-1 substrates and interaction proteins are localized in various intracellular organelles including nucleus and secreted extracellularly; (2) Caspase-1 may get activated in situ in the nucleus in response to intra-nuclear danger signals; (3) Caspase-1 cleaves its substrates in exocytotic secretory pathways including exosomes to propagate inflammation to neighboring and remote cells; (4) Most of caspase-1 substrates are upregulated in coronary artery disease regardless of their subcellular localization but the majority of metabolic diseases cause no significant expression changes in caspase-1 nuclear substrates; and (5) In coronary artery disease, majority of upregulated caspase-1 extracellular substrate-related pathways are involved in induction of inflammation; and in contrast, upregulated caspase-1 nuclear substrate-related pathways are more involved in regulating cell death and chromatin regulation.ConclusionsOur identification of novel caspase-1 trafficking sites, nuclear and extracellular inflammasomes, and extracellular caspase-1-based inflammation propagation model provides a list of targets for the future development of new therapeutics to treat cardiovascular diseases, inflammatory diseases, and inflammatory cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0351-5) contains supplementary material, which is available to authorized users.

Thrombus leukocytes exhibit more endothelial cell-specific angiogenic markers than peripheral blood leukocytes do in acute coronary syndrome patients, suggesting a possibility of trans-differentiation: a comprehensive database mining study

“…Although the research paper associated with this GEO dataset has not been published from Dr. Luscher’s team in the University Hospital Zurich, Switzerland, based on similar publications on isolation of Tregs [44], CD14 + monocytes and CD66B + granulocytes [45] in coronary thrombi of patients with ACS and microarray profiling [46] from this highly productive team, we were fully convinced that the high quality of GSE19339 dataset and related technologies in coronary thrombus leukocyte isolation and microarray profiling are trustable. In addition, to determine the functional significance of upregulated genes, we examined the subcellular localization of the 15 upregulated genes including FLT1, NRP1, ANGPTL4, NRP2, VEGFA, EPAS1, JAG1, TEK, JUN, NOTCH3, TIE1, KDR, HIF1A, ANGPT2, and PGF using two highly reliable databases (COMPARTMENTS subcellular location database and UniProtKB/Swiss-Prot location database) as we reported [10] (Fig. 6a).…”

“…To determine whether inflammatory factors assist angiogenic cells in recognizing cardiovascular disease risk factors such as hyperlipidemia, hyperglycemia, obesity, metabolic syndrome, hypertension, smoke, and hyperhomocystemia [7], we recently reported a series of findings on the expression and roles of innate immune/inflammation sensor caspase-1/inflammasome [8–10] in regulating angiogenic cells, including endothelial cell [11–15], Sca-1 + progenitor cell [16, 17]. We also found that CD4 + Foxp3 + regulatory T cells (Tregs) inhibit vascular inflammation [18–20] and that Treg-generated newly classified responsive immunosuppressive cytokine interleukin-35 (IL-35) [21] suppresses EC activation [22].…”

Prdx4 limits caspase‐1 activation and restricts inflammasome‐mediated signaling by extracellular vesicles

“…An extracellular role of the inflammasome and its components has already been suggested (Baroja-Mazo et al, 2014;Franklin et al, 2014;Mitra et al, 2015). Moreover, IL-1b, caspase-1, and other inflammasome components have been described to localize to exosomes (Qu et al, 2007) and it was suggested from a meta-analysis of proteomic and protein interaction data that caspase-1 cleaves its substrates to propagate inflammation to neighboring and remote cells in extracellular vesicles (Wang et al, 2016). Moreover, IL-1b, caspase-1, and other inflammasome components have been described to localize to exosomes (Qu et al, 2007) and it was suggested from a meta-analysis of proteomic and protein interaction data that caspase-1 cleaves its substrates to propagate inflammation to neighboring and remote cells in extracellular vesicles (Wang et al, 2016).…”

“…In particular, ASC specks have been shown to accumulate in the extracellular space, where they promoted IL-1b maturation (Franklin et al, 2014). Moreover, IL-1b, caspase-1, and other inflammasome components have been described to localize to exosomes (Qu et al, 2007) and it was suggested from a meta-analysis of proteomic and protein interaction data that caspase-1 cleaves its substrates to propagate inflammation to neighboring and remote cells in extracellular vesicles (Wang et al, 2016). Yet, the exact role of their presence in the compartment remained unclear.…”

Uremic toxins are conditional danger- or homeostasis-associated molecular patterns

“…As we reported previously, for inflammation-privileged tissues, such as cardiovascular tissues in which inflammasome component genes are not constitutively expressed, TLRs work in synergy with upregulated cytosol-located sensing receptor families including NLRs (NOD (nucleotide binding and oligomerization domain)-like receptors) (30). In the cytosol, nucleus and extracellular compartment as we most recently reported, these inflammasome components and pro-caspase-1 assemble into a protein complex termed inflammasome, which subsequently activates caspase-1 after recognizing endogenous DAMPs (31). In this way, TLRs mediate upregulation, activation of a range of inflammatory genes and acceleration of vascular inflammation and atherosclerosis (2,32).…”