Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon.

Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation.

Caspase-4 and -5 Biology in the Pathogenesis of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract, associated with high levels of inflammatory cytokine production. Human caspases-4 and -5, and their murine ortholog caspase-11, are essential components of the innate immune pathway, capable of sensing and responding to intracellular lipopolysaccharide (LPS), a component of Gram-negative bacteria. Following their activation by LPS, these caspases initiate potent inflammation by causing pyroptosis, a lytic form of cell death.

Identification of TLR2 Signalling Mechanisms Which Contribute to Barrett's and Oesophageal Adenocarcinoma Disease Progression.

Chronic inflammation plays an important role in the pathogenesis of oesophageal adenocarcinoma (EAC) and its only known precursor, Barrett's oesophagus (BE). Recent studies have shown that oesophageal TLR2 levels increase from normal epithelium towards EAC. TLR2 signalling is therefore likely to be important during EAC development and progression, which requires an inflammatory microenvironment.

Evaluating Host Responses to Helicobacter pylori Using ELISA and Western Blot.

Western blot and enzyme-linked immunosorbent assay (ELISA) are antibody-mediated techniques which are widely used for the detection and characterization of alterations in host protein expression following H. pylori infection . Both techniques are highly specific and sensitive for protein detection, with Western blot detection sensitivity as low as picogram amounts of the protein of interest, while the typical ELISA detection range is 0.

Regulation, Activation and Function of Caspase-11 during Health and Disease.

Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 activation is triggered by its interaction with lipopolysaccharide (LPS) from Gram-negative bacteria.

Caspase-4: A Therapeutic Target for Peptic Ulcer Disease.

Peptic ulcers are caused by the interaction between bacterial and host factors. This study demonstrates enhanced expression of caspase-4 in peptic ulcer patient biopsies, indicating that pyroptosis and noncanonical inflammasome activity may be processes involved in peptic ulcer disease. We show that primary murine macrophages infected with upregulate caspase-11 (the ortholog of human caspase-4), activate caspase-1, and secrete IL-1β.

Caspase-11 promotes allergic airway inflammation.

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E (PGE) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation.

Guardians of the Cell: Effector-Triggered Immunity Steers Mammalian Immune Defense.

The mammalian innate immune system deals with invading pathogens and stress by activating pattern-recognition receptors (PRRs) in the host. Initially proposed to be triggered by the discrimination of defined molecular signatures from pathogens rather than from self, it is now clear that PRRs can also be activated by endogenous ligands, bacterial metabolites and, following pathogen-induced alterations of cellular processes, changes in the F-actin cytoskeleton. These processes are collectively referred to as effector-triggered immunity (ETI).

Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis.

Murine inflammatory caspase-11 has an important role in intestinal epithelial inflammation and barrier function. Activation of the non-canonical inflammasome, mediated by caspase-11, serves as a regulatory pathway for the production of the pro-inflammatory cytokines IL-1β and IL-18, and has a key role in pyroptotic cell death. We have previously demonstrated a protective role for caspase-11 during dextran sulphate sodium (DSS)-induced colitis, however the importance of caspase-11 during colorectal tumour development remains unclear.

Suppression of human alloreactive T cells by linear tetrapyrroles; relevance for transplantation.

The main limitation to successful transplantation is the antigraft response developed by the recipient immune system, and the adverse side effects of immunosuppressive agents which are associated with significant toxicity and counter indications such as infection and cancer. Furthermore, immunosuppressants do little to prevent ischemia-reperfusion injury during the transplantation procedure itself hence there is a growing need to develop novel immunosuppressive drugs specifically aimed at prolonging graft survival. Linear tetrapyrroles derived from the breakdown of mammalian heme have been shown in numerous studies to play a protective role in allograft transplantation and ischemia-reperfusion injury; however, commercial sources of these products have not been approved for use in humans.

Protective role for caspase-11 during acute experimental murine colitis.

Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1β and IL-18. Noncanonical inflammasome activity occurs during host defense against Gram-negative bacteria and in models of acute septic shock. We propose that the noncanonical inflammasome is activated in mice during acute intestinal inflammation elicited by dextran sodium sulfate (DSS), a model of experimental colitis.

Caspase crosstalk: integration of apoptotic and innate immune signalling pathways.

The caspase family of cysteine proteases has been functionally divided into two groups: those involved in apoptosis and those involved in innate immune signalling. Recent findings have identified 'apoptotic' caspases within inflammasome complexes and revealed that 'inflammatory' caspases are capable of inducing cell death, suggesting that the earlier view of caspase function may have been overly simplistic. Here, I review evidence attributing nonclassical functions to many caspases and propose that caspases serve as critical mediators in the integration of apoptotic and inflammatory pathways, thereby forming an integrated signalling system that regulates cell death and innate immune responses during development, infection, and homeostasis.

Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation.

Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1β secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1β in antigen-presenting cells.

Rab39a binds caspase-1 and is required for caspase-1-dependent interleukin-1beta secretion.

Interleukin-1beta (IL-1beta) is an important pro-inflammatory cytokine that is secreted by unconventional means in a caspase-1-dependent manner. Using a one-step immunoprecipitation approach to isolate endogenous caspase-1 from the monocytic THP1 cell line, we identified previously undescribed binding partners using mass spectrometry. One of the proteins identified was Rab39a, a member of the Rab GTPase family, a group of proteins that have important roles in protein trafficking and secretion.

Bicaudal is a conserved substrate for Drosophila and mammalian caspases and is essential for cell survival.

Members of the caspase family of cysteine proteases coordinate cell death through restricted proteolysis of diverse protein substrates and play a conserved role in apoptosis from nematodes to man. However, while numerous substrates for the mammalian cell death-associated caspases have now been described, few caspase substrates have been identified in other organisms. Here, we have utilized a proteomics-based approach to identify proteins that are cleaved by caspases during apoptosis in Drosophila D-Mel2 cells, a subline of the Schneider S2 cell line.

Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.

Many currently used and candidate vaccine adjuvants are particulate in nature, but their mechanism of action is not well understood. Here, we show that particulate adjuvants, including biodegradable poly(lactide-co-glycolide) (PLG) and polystyrene microparticles, dramatically enhance secretion of interleukin-1beta (IL-1beta) by dendritic cells (DCs). The ability of particulates to promote IL-1beta secretion and caspase 1 activation required particle uptake by DCs and NALP3.

TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity.

Significant advances in our understanding of innate immunity have been made following the identification of three families of pathogen sensors: Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). Members of the TLR family recognize bacteria, viruses, fungi and protozoa; NLRs with known functions detect bacteria, and RLRs are anti-viral. It is likely that interplay between these families ensures the efficient co-ordination of innate immune responses, through either synergistic or co-operative signalling.

Caspase-dependent inactivation of proteasome function during programmed cell death in Drosophila and man.

The caspase family of cysteine proteases plays a conserved role in the coordinate demolition of cellular structures during programmed cell death from nematodes to man. Because cells undergoing programmed cell death in nematodes, flies, and mammals all share common features, this suggests that caspases target a common set of cellular structures in each of these organisms. However, although many substrates for mammalian caspases have been identified, few substrates for these proteases have been identified in invertebrates.

Interchain proteolysis, in the absence of a dimerization stimulus, can initiate apoptosis-associated caspase-8 activation.

Caspases coordinate the internal demolition of the cell that is seen during apoptosis. Proteolytic processing of caspases is observed during apoptosis, and this correlates with conversion of inactive caspase proenzymes into their active two-chain forms. However, recent studies have suggested that caspase-8 is activated through dimerization and that interchain proteolysis is not sufficient for activation of this caspase.

Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes.

The Apaf-1 apoptosome is a multi-subunit caspase-activating scaffold that is assembled in response to diverse forms of cellular stress that culminate in apoptosis. To date, most studies on apoptosome composition and function have used apoptosomes reassembled from recombinant or purified proteins. Thus, the precise composition of native apoptosomes remains unresolved.