However, these techniques remain limited in their ability to anal

However, these techniques remain limited in their ability to analyse

cell motility and interactions (e.g. between NKT cells and DCs) over extended time and distances in intact tissue, Ponatinib cost and to distinguish between individual cells in a labelled cell aggregate. As stated by Dr Ron Germain, ‘the most significant advance currently undergoing development in intravital imaging of the immune system is the combination of molecular imaging with measurements of the dynamics of single cells’.[54] The long-term goal is to attribute cellular movement and positioning to causal changes in cell signalling and gene expression in vivo. To achieve this goal, improvements in cell imaging are required and may include increases in the number of different colours used, tissue volume examined and number of cells imaged, duration of imaging sessions, and use of subcellular probes.[51, 54] The successful application of these novel technologies will depend largely on the development of new computer algorithms to analyse complex data sets of system biology approaches, including computer simulations.[135, 136] Additional studies may benefit from the imaging of higher quality sample preparations from less well-characterized tissues (e.g. gastrointestinal tract, pancreas, spleen and lung). Most importantly, it is envisaged that better diagnostic

procedures be achieved in the clinic by introducing Cisplatin order miniaturized imaging instruments and light delivery systems in endoscopes or implantable devices.[54] This work was supported by grants from the National Institutes

of Health, USA, R01 CA100660 and R01 AA020864 (VK) and from the Juvenile Diabetes Research Foundation (JDRF) grants 24-2007-388 (TLD) and 24-2007-362 (VK). Additional support was provided by the Canadian Institutes of Health Research grant MOP 64386 (TLD). PIK3C2G The authors declare no conflict of interest. “
“Cephalosporin-resistant Escherichia coli has been increasingly reported worldwide. In this study, 32 cephalosporin resistant E. coli isolates identified from cancer patients in Cairo, Egypt in 2009–2010 were analyzed. Twenty-three were of phylogenetic group D, seven A and one each B1 and B2. By rep-PCR 15 phylogroup D isolates were grouped in four clusters, one with sequence type (ST) 405 and three ST68. Seventeen isolates showed single patterns. blaCTX-M-15 and aac(6′)-Ib-cr were the most common resistance determinants. blaOXA-48 and blaVIM were also detected. Multidrug resistant E. coli seriously affects healthcare, especially in immunocompromised hosts, such as cancer patients. Escherichia coli is a major cause of both community and healthcare-associated infections [1, 2]. Extra-intestinal infections due to E. coli increase morbidity, mortality, and healthcare costs in hospitalized patients [3]. Their impact can be especially severe in immunocompromised patients, such as cancer patients receiving chemotherapy [4]. Extended spectrum β-lactamases, AmpC and carbapenemase-producing E.

In both study groups, we found low but detectable levels of CD19+

In both study groups, we found low but detectable levels of CD19+ cells in both circulating blood and

spleen buy Buparlisib at time of termination. This is consistent with earlier reports showing that in LIP the rate of B cell expansion is much lower than that of T cells [36]. Also, the total IgG levels were at a detectable, though low level in both groups, with no significant difference between the groups (Fig. 3A). There was also no significant difference in the serum levels of B cell-activating factor (BAFF), a factor linked to T cell-independent B cell-mediated autoimmunity in Aire−/− mice [27] (data not shown). We then tested the recipients for the presence of autoantibodies against colon, ileum, gastric mucosa, pancreas, kidneys, liver, retina, ovaries and salivary glands. Two kinds of autoantibodies were found in the recipients: autoantibodies targeted to retinal cells in the eye or to smooth muscle cells in the

intestinal walls. In the Aire group, 10 of 10 animals stained positive for either one or both of these autoantibodies. Only four animals of 11 in the control group had autoantibodies targeted https://www.selleckchem.com/products/epacadostat-incb024360.html to smooth muscle, and none had autoantibodies targeted to retina. No detectable anti-nuclear antibodies were found in either of the recipient groups. One of the Aire−/− donors stained positive for autoantibodies against both retina and smooth muscle, and all recipients of cells from this donor had similar autoantibodies. Another Aire−/− donor was negative for all autoantibodies tested, but six of six recipients of cells from this donor still became positive for smooth-muscle autoantibodies. None of the control group donors stained positive for autoantibodies (Fig. 3B). These data indicate that LIP of cells from Aire−/− donors both expanded pre-existing autoreactivity about and revealed new autoreactive clones. In LIP, the gut commensal flora is an important source of antigens driving the proliferation, and in adoptive transfer

of T cells to a lymphopenic host, the most common pathology is colitis [37]. Therefore, because the systemic or organ-specific autoimmune manifestations in the recipients were so modest, we next analysed whether the recipients developed colitis. At the time of termination, the recipients in the Aire-group had a significantly higher proportion of T cells in the mononuclear fraction isolated from the mesenteric lymph nodes (Fig. 4A). However, histological analysis of the colon tissue sections showed no difference in the degree of lymphocyte infiltration between the groups. Similarly, although the amount of TCR Cα mRNA was slightly higher in the colon samples from the Aire-group, the difference was not statistically significant (P = 0.098).

[Eur J Immunol 2013 43, 2126–2137] show that the NLRP3 inflam

[Eur. J. Immunol. 2013. 43, 2126–2137] show that the NLRP3 inflammasome contributes to oxidative DNA damage. In addition, activation of the NLRP3 inflammasome modulates a number of pathways involved in DNA damage repair, cell cycle, and apoptosis, suggesting a novel role for the NLRP3 inflammasome in DNA damage responses following cellular stress. From microbes to radiation and other carcinogens, the environment in which we live can seem like a veritable minefield. Fortunately, the cells and molecules of the innate immune system have evolved, along with cell-intrinsic processes, to respond swiftly in defense of our cellular and genomic integrity. These multilayered and redundant mechanisms combat

the potentially deleterious effects of diverse environmental stresses by promoting either resolution or cell find protocol death in an attempt to return to homeostasis. An important component of the innate immune system is the NLRP3 inflammasome. Following detection of cellular damage,

the cytoplasmic nucleotide-binding domain leucine-rich repeat containing (NLR) molecule NLRP3 forms a multiprotein complex, along with the adaptor molecule ASC and the cysteine protease caspase-1 [1]. This process culminates in the activation of caspase-1 and the subsequent maturation and secretion of the proinflammatory cytokines, IL-1β and IL-18 [2-5]. Interestingly, oligomerization and activation of the NLRP3 inflammasome can be induced by a heterogeneous collection of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively), although the means find more by which this occurs is unclear. It has been proposed that these inflammasome activating signals actually

work indirectly via a common downstream ligand, such as reactive oxygen species (ROS) [6, 7] generated following mitochondrial damage [8, 9]. Cellular cation fluxes, including a potassium efflux and a calcium influx, have also been shown to be critical RG7420 for activation of the NLRP3 inflammasome [10, 11]. In addition to its role in immune surveillance, dysregulation of the NLRP3 inflammasome has been reported to contribute to the pathogenesis of a number of human diseases that have an underlying component of chronic inflammation, such as type 2 diabetes mellitus, atherosclerosis, and inflammatory bowel disease [12]. As well, mutations within the gene encoding NLRP3 have been associated with the autoinflammatory cryopyrin-associated periodic syndromes [13]. Such widespread effects underscore the complexity of pathways through which the well-studied NLRP3 inflammasome functions, and emerging literature on the subject indicates there is much left to learn. In this issue of the European Journal of Immunology, Licandro et al. [14] explore noncanonical roles for the NLRP3 inflammasome, i.e. proinflammatory cytokine-independent effects under conditions of cellular stress.

In the next subsections, we will illustrate the protective effect

In the next subsections, we will illustrate the protective effects mediated by Ab–FcR interactions in the context of a selection of infections with intracellular bacteria and parasites. Legionella pneumophila are Gram-negative bacteria that, when inhaled, can infect and replicate within alveolar macrophages and cause a severe form of pneumonia known as Legionnaire’s disease. Upon contact with the macrophage, L. pneumophila uses its Icm/Dot type IV secretion system (T4SS)

to inject a large number of effector proteins into the cytosol of the selleck chemicals host cell 63. This promotes phagocytosis and modulates trafficking within the host cell, resulting in the evasion of phagolysosomal fusion and the establishment of a replication-permissive vacuole 64. We have recently shown that this Icm/Dot T4SS-mediated subversion of trafficking within the host cell does not take place in the presence of specific Abs as, in such circumstances, L. pneumophila is targeted to lysosomes and can no longer replicate intracellularly 65. Thus, opsonized L. pneumophila are targeted see more into

degradative pathways, indicating that specific Abs can effectively oppose the events initiated by the T4SS. The opsonization of L. pneumophila with specific Abs does not interfere with the function of the T4SS itself but it is actually the cross-linking of activating FcRs on the surface of macrophages that renders these host cells nonpermissive for intracellular replication of L. pneumophila. The importance of FcR triggering for this protective effect was demonstrated both in vitro and in vivo; however, the lysosomal targeting of L. pneumophila is not simply a direct consequence of FcR-mediated endocytosis and subsequent phagolysosomal fusion since macrophages, which had received an FcR trigger before infection with nonopsonized bacteria, also effectively targeted L. pneumophila to lysosomal compartments and hence did not permit

their intracellular replication 65. These Telomerase results suggest that FcR cross-linking induces a signaling cascade that effectively counteracts the modulation of host cell trafficking by Legionella effectors and redirects the bacteria to lysosomes where they are degraded. By arresting phagosome maturation M. tuberculosis survives and replicates in membrane-bound compartments in macrophages 66. Ab responses have long been believed to play a negligible or even detrimental role in protection against this intracellular bacterium, whereas cell-mediated immunity was assigned to be crucial in resolving infections. Nevertheless, newer findings implicate a role for Abs in protection against mycobacterial infections 67, 68. mAbs of the IgG3 or IgG1 subclass recognizing surface Ags of M. tuberculosis such as the carbohydrate lipoarabinomannan (LAM) have been shown to prolong survival of intratracheally or intravenously M.

39 The institutional ethical committee

39 The institutional ethical committee BKM120 approved this study. The statistical significance of the results was determined using Student’s t-test. The results are presented as mean ± standard deviation (SD). The 16-kDa recombinant protein coded by Rv2626c was expressed in the E. coli BL21plys (DE3) strain and purified using metal affinity chromatography, giving a yield of 10 mg/l culture. The purified rRv2626c when analysed by SDS–PAGE (Fig. 1) or even after silver staining (data not shown) did not reveal any major contaminating protein band. The endotoxin content in the purified recombinant protein was checked using the amoebocyte lysate

assay and was found to be extremely low (0·05 pg/μg of protein). Previous studies have revealed that Rv2626c is a secretory protein, indicating that Rv2626c could influence the host immune response by interacting with macrophage surface receptors. In order to assess the ability of rRv2626c to bind to the surface of RAW 264·7 macrophages,

cells were incubated Bcl-2 inhibitor with 10 μg of rRv2626c for various times and the bound rRv2626c was investigated using anti-rRv2626c antibody in a FACS analysis. The binding of rRv2626c with macrophages could be seen as early as 5–10 min after the start of incubation, and remained noticeably high until 60 min (Fig. 2). It could be seen (Fig. 2, brown curve) that the binding of rRv2626c to macrophages was inhibited when the cells were incubated with anti-Rv2626c antibody preincubated with rRv2626c. This clearly indicates that rRv2626c binds with high affinity and specificity to the surface of RAW 264·7 macrophages. Similar observations were obtained for phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages (data not shown). Having demonstrated binding of Rv2626c to the surface of murine macrophage cells cultured in vitro, the ability of rRv2626c to induce NO production via de novo expression of iNOS in the macrophages was assessed. RAW 264·7 macrophages

were stimulated with different concentrations of rRv2626c aminophylline protein (Fig. 3a; bars 3, 4 and 5). Stimulants such as LPS and IFN-γ were used as positive controls (Fig. 3a; bar 2) for NO production and iNOS expression (Fig. 3b; lane 2) in RAW 264·7 macrophages. NO production increased in RAW 264·7 macrophages with the addition of rRv2626c in a dose-dependent manner (Fig. 3a; bars 3, 4 and 5). Similar observations were obtained in J774·1 macrophages (data not shown). NO production by the cells was not observed when cells were stimulated with proteinase K-treated rRv2626c protein (Fig. 3a; bar 6), indicating that the NO production was specifically attributable to the presence of rRv2626c and was not a result of endotoxin contamination in the protein preparation. This increased NO production correlated well with the increase in iNOS expression in cells stimulated with rRv2626c (Fig. 3b; lane 3) as compared with the unstimulated group (Fig. 3b; lane 1).

heilmannii antigen-specific immune responses mediated by PP is di

heilmannii antigen-specific immune responses mediated by PP is dispensable for the formation of gastric lymphoid follicles. This work was supported, in part, by grants for the Global COE

Program (F031), for Scientific Research in Priority Areas ‘Genome’ (T.A. and M.Y.), for the Education Program for Specialized Clinicians in the Support Program (K.N.) from the Ministry of Education, selleckchem Culture, Sports, Science, and Technology of Japan, and for the COE research support program from Hyogo prefecture (T.A.). “
“Due to clinical efficacy and safety profile, extracorporeal photochemotherapy (ECP) is a commonly used cell treatment for patients with cutaneous T cell lymphoma (CTCL) and graft-versus-host disease (GVHD). The capacity of ECP to induce dendritic antigen-presenting cell (DC)-mediated selective immunization or immunosuppression suggests a novel mechanism involving pivotal cell signalling processes that have yet to be clearly identified as related to this procedure. In this study we employ two model systems

of ECP to dissect the role of integrin signalling and adsorbed plasma proteins in monocyte-to-DC differentiation. We demonstrate that monocytes that were passed through protein-modified ECP plates adhered transiently to plasma proteins, including fibronectin, adsorbed to the plastic ECP plate and activated signalling pathways Apoptosis antagonist that initiate monocyte-to-DC conversion. Plasma protein adsorption facilitated 54·2 ± 4·7% differentiation, while fibronectin supported 29·8 ± 7·2% differentiation, as detected by DC phenotypic expression of membrane CD80 and CD86, as well as CD36, human leucocyte antigen D-related Dynein (HLA-DR) and cytoplasmic CD83. Further, we demonstrate the ability of fibronectin and other plasma proteins to act through cell adhesion via the ubiquitous arginine–glycine–aspartic (RGD) motif to drive monocyte-to-DC differentiation, with high-density RGD substrates supporting 54·1 ± 5·8% differentiation via αVβ3 and α5β1integrin signalling. Our results demonstrate that plasma protein binding integrins and plasma proteins operate through specific binding domains to induce monocyte-to-DC

differentiation in ECP, providing a mechanism that can be harnessed to enhance ECP efficacy. “
“Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden Department of Neuroscience, Physiology and Pharmacology, University College London, UK Signal regulatory protein α (SIRPα) and its cognate ligand CD47 have been documented to have a broad range of cellular functions in development and immunity. Here, we investigated the role of SIRPα–CD47 signalling in invariant NKT (iNKT) cell responses. We found that CD47 was required for the optimal production of IFN-γ from splenic iNKT cells following exposure to the αGalCer analogue PBS-57 and in vivo infection of mice with Leishmania donovani.

In fact we detected virtually no IL-17A+ cells within the Foxp3+

In fact we detected virtually no IL-17A+ cells within the Foxp3+ population. While not completely unexpected, because Foxp3 can inhibit some of the transcriptional activity of RORγt,57 Foxp3+ IL-17A+ cells have been previously reported.58 Our observation that G-1 induces

IL-10 expression in Foxp3+ RORγt+ hybrid T cells suggests that, in addition to generating IL-10 production in populations already localized at the site of inflammation, G-1 may also enhance the suppressive YAP-TEAD Inhibitor 1 function of Treg populations drawn in from the circulation. Such a response would not be unprecedented as T-bet-induced CXCR3 expression in Foxp3+ cells has been shown to play a role in targeting Treg cells to sites of Th1-type inflammation.59 If IL-10 can be stably induced in hybrid T-cell populations following in vivo G-1 treatment, their suppressive activity may be enhanced as they are

recruited to sites of ongoing inflammation. Numerous attempts have been made to harness the immunosuppressive properties of IL-10 for therapeutic benefit, many of which have been based on the use of biologics.25 To our knowledge, this is the first evidence that a synthetic small molecule can shift the balance along the Treg–Th17 axis in favour of IL-10 production, in PD-0332991 manufacturer this case by acting directly on T-cell populations. These data build on previous results demonstrating that dexamethasone and retinoic acid can elicit IL-10 from polyclonally stimulated naive T cells when IL-4, IL-12 and IFN are neutralized.60 Also worth noting is the fact that it is becoming increasingly clear that GPER probably plays a smaller role in the majority of classical estrogen responses, such as

uterine imbibition, as compared with its better known counterpart ERα.40 Hence G-1 may be associated with a more tolerable adverse effect profile. Our findings suggest that the membrane-permeable small molecule G-1 may serve as a novel T-cell-targeted immunosuppressive agent in settings where large populations of Th17 cells exist, for example in rheumatoid arthritis, inflammatory bowel disease, or psoriasis. G-1 may also prove useful for in vitro generation of IL-10-producing cells for adoptive immunotherapy. Future studies delineating the specific Mirabegron signalling mechanisms and targets of G-1 and other related compounds will be seminal to the continued development of this new class of immunoregulatory estrogenic small molecules. The selectivity of G-139,53 and its attractive pharmacological properties38 make this compound a strong candidate for pharmaceutical development, paving the way for the development of novel T-cell targeted immunotherapeutics. This work was supported by National Institutes of Health grants R01 CA116662, CA118743 and CA127731 (E.R.P.). Data were generated in the Flow Cytometry Shared Resource Center supported by the University of New Mexico Health Sciences Center and the University of New Mexico Cancer Center.

Cells were cultured in IMDM supplemented with glutamax, 100 U/mL

Cells were cultured in IMDM supplemented with glutamax, 100 U/mL penicillin, 100 μg/mL streptomycin (Invitrogen, Breda, The Netherlands) and 10% human serum at 37°C and 5% CO2. After 7 days of incubation, cells were stained for further analysis on the flow-cytometer. Cells were stained for the following Dactolisib surface markers; CD8-APC (DakoCytomation, Heverlee, Belgium), CD3-PerCP and CD4-PE (BD Biosciences), washed in PBS 0.1% BSA (Sigma Aldrich, Zwijndrecht, The Netherlands), fixed in 1% paraformaldehyde (Pharmacy LUMC, The Netherlands) and acquired on an LSRII with HTS plate loader (BD Biosciences).

Analysis was performed using FACS DIVA software (BD Biosciences). Live lymphocyte gated cells combined with gating

of CD3+ CD4+ and CD3+ CD8+ T cells were analyzed for proliferation using CFSE dye dilution. The Δ geometric mean was used as a measure of proliferation and calculated as follows: Δ geometric mean=geometric mean (non-proliferated CP-868596 molecular weight cells) – geometric mean (total cells). The Δ geometric mean was then used to calculate the “relative proliferation”, which is the percentage of maximal proliferation (PHA) corrected for spontaneous proliferation (HIV-1 p17 Gag77–85) ((Δ geometric mean sample − Δ geometric mean control medium)/(Δ geometric mean PHA − Δ geometric mean control medium))×100%=% of maximal proliferation. The cut-off value for a positive proliferative response was arbitrarily set at 10% relative proliferation in order to limit Tau-protein kinase the number of candidate epitopes to be evaluated in subsequent experiments 30. IFN-γ concentration in cellular supernatants was detected using ELISA (U-CyTech, Utrecht, The Netherlands) as previously described 59. This work was supported by a grant from the Foundation Microbiology Leiden, the European Commission within the sixth Framework Program (FP6), the Bill and Melinda Gates

Foundation, TI Pharma (project D-101-1), Grand Challenges in Global Health (GC6♯74, GC12♯82), ISA Pharmaceuticals and TBVAC contract no. LSHP-CT-2003-503367 (the text represents the authors’ views and does not necessarily represent a position of the Commission who will not be liable for the use made of such information). We thank Corine Prins, Sandra Arend, Michèl R. Klein, Willem Verduijn and his colleagues for their support. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. “
“Eosinophils have recently been demonstrated capable of localizing to lymph nodes that drain mucosal surfaces, in particular during T helper 2 (Th2) responses.

CNV of

NKG2C was assessed by a PCR method based on the ap

CNV of

NKG2C was assessed by a PCR method based on the approach used by Miyashita et al. [43], with modifications. Briefly, homo- and heterozygosity for the NKG2C gene and its deletion were determined by a single Selleckchem PLX4032 PCR that yields amplicons of different lengths in each genotype. This is achieved by means of two primer pairs recognizing sequence motifs specific for, either NKG2C, or the gene arrangement resulting from its deletion [60]. In one child participating in the study this analysis could not be performed. Comparisons of categorical variables among study groups were performed using the chi-square or Fisher exact test, as appropriate. Continuous variables were compared using the Mann–Whitney U test. A p value <0.05 was considered statistically significant.

Spearman’s rank correlation coefficient was used to evaluate the association between continuous variables. Multivariate analysis was carried out using linear regression analysis; the dependent variables were subjected to logarithmic transformation prior to inclusion in the regression model. This work was supported by grants from Plan Nacional de I+D (SAF2010–22153-C03), and EU SUDOE program (SOE2/P1/E341). A.M. is supported by Asociación Española Contra el Cáncer (AECC). We thank Gemma Heredia and María Cañizares for their excellent technical assistance, and Joan Vila for his expert advice in statistical analysis. We are grateful to patients and their families for generously accepting to participate in this study. The authors declare no financial or commercial conflict Crizotinib chemical structure of interest. Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Figure 1. Variable NKG2C surface expression intensity in NK cells. Table 1. Clinical findings at birth and NK-cell immunophenotype in children with symptomatic congenital infection. Table 2. Summary of multivariate linear regression analysis. “
“To target gestational diabetes mellitus (GDM) by means of temporal variation Pregnenolone in pregnancy-associated plasma protein A (PAPP-A) and soluble human leukocyte antigen-G (sHLA-G). Retrospective analysis of PAPP-A and sHLA-G blood levels in historical samples of 112 GDM and 112 controls,

drawn at first trimester, and prospective study in 18 GDM and 105 controls collected in triplicate along the pregnancy. Six hundred and sixty-five samples were analyzed. Gestational diabetes mellitus had significantly lower first-trimester PAPP-A concentrations than controls (2343 ± 1519 versus 2996 ± 1955 mU/mL, in retrospective brunch and 2490.57 ± 1828.52 versus 3240.84 ± 1930.69 mU/L in prospective one, P < 0.001). First-trimester sHLA-G level was significantly lower in GDM than in controls (52.88 ± 59.69 versus 66.81 ± 50.14 ng/mL, P < 0.001) and increased during gestation in diabetic women showing an opposite trend with respect to the controls. PAPP-A and sHLA-G are independent markers of GDM. Quantitative variations during pregnancy help to early unravel the onset of GDM.

[Eur J Immunol 2013 43, 2126–2137] show that the NLRP3 inflam

[Eur. J. Immunol. 2013. 43, 2126–2137] show that the NLRP3 inflammasome contributes to oxidative DNA damage. In addition, activation of the NLRP3 inflammasome modulates a number of pathways involved in DNA damage repair, cell cycle, and apoptosis, suggesting a novel role for the NLRP3 inflammasome in DNA damage responses following cellular stress. From microbes to radiation and other carcinogens, the environment in which we live can seem like a veritable minefield. Fortunately, the cells and molecules of the innate immune system have evolved, along with cell-intrinsic processes, to respond swiftly in defense of our cellular and genomic integrity. These multilayered and redundant mechanisms combat

the potentially deleterious effects of diverse environmental stresses by promoting either resolution or cell Selleckchem Idasanutlin death in an attempt to return to homeostasis. An important component of the innate immune system is the NLRP3 inflammasome. Following detection of cellular damage,

the cytoplasmic nucleotide-binding domain leucine-rich repeat containing (NLR) molecule NLRP3 forms a multiprotein complex, along with the adaptor molecule ASC and the cysteine protease caspase-1 [1]. This process culminates in the activation of caspase-1 and the subsequent maturation and secretion of the proinflammatory cytokines, IL-1β and IL-18 [2-5]. Interestingly, oligomerization and activation of the NLRP3 inflammasome can be induced by a heterogeneous collection of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively), although the means LDK378 by which this occurs is unclear. It has been proposed that these inflammasome activating signals actually

work indirectly via a common downstream ligand, such as reactive oxygen species (ROS) [6, 7] generated following mitochondrial damage [8, 9]. Cellular cation fluxes, including a potassium efflux and a calcium influx, have also been shown to be critical Staurosporine order for activation of the NLRP3 inflammasome [10, 11]. In addition to its role in immune surveillance, dysregulation of the NLRP3 inflammasome has been reported to contribute to the pathogenesis of a number of human diseases that have an underlying component of chronic inflammation, such as type 2 diabetes mellitus, atherosclerosis, and inflammatory bowel disease [12]. As well, mutations within the gene encoding NLRP3 have been associated with the autoinflammatory cryopyrin-associated periodic syndromes [13]. Such widespread effects underscore the complexity of pathways through which the well-studied NLRP3 inflammasome functions, and emerging literature on the subject indicates there is much left to learn. In this issue of the European Journal of Immunology, Licandro et al. [14] explore noncanonical roles for the NLRP3 inflammasome, i.e. proinflammatory cytokine-independent effects under conditions of cellular stress.