The main alterations in the immune system with age include reduce

The main alterations in the immune system with age include reduced humoral responses after vaccination or infection, decreases in dendritic cells efficiency to activate T and B cell populations, declines in the

generation of new naive T and B cells, and in natural killer (NK) cells’ ability to kill tumor cells (Aw et al., 2007; Hakim & Gress, 2007; Candore et al., 2008). Because of these changes, the frequency and severity of infectious disease, chronic inflammatory disorders, autoimmunity, and cancer incidence are hallmarks for immunosenescence (Gomez et al., 2008; Provinciali, 2009). The increase in the proportion of aged individuals globally and especially in western countries (World Population Prospects, 2008) Peptide 17 molecular weight necessitates the search for innovative strategies to thwart the effects of immunosenescence. These strategies should be focused on preventing the deviations or restoring the function of the immune system in older individuals. Interventions such as specific vaccination against viruses, anti-inflammatory treatments, nutrition interventions, exercise, and pre- and probiotic have been suggested to restore the immune functions in

the GSK126 in vitro elderly (Candore et al., 2008; Mocchegiani et al., 2009). The gastrointestinal tract is the main entry for bacterial cells through foods and drinks and is the site for presenting millions of antigens to the gut-associated-lymphoid tissues, which contains 70% of the immunoglobulin-producing cells. The intake of specific probiotic

bacteria has been reported to enhance the immune response in a strain-specific manner (Nova et al., 2007; Borchers et al., 2009). Earlier studies have reported that specific strains of lactic acid bacteria have immune-enhancing properties (Nova et al., C-X-C chemokine receptor type 7 (CXCR-7) 2007; Candore et al., 2008). However, probiotic bacteria have often been assessed in milk, fermented milks, or as dietary supplements. Therefore, we decided to investigate the effect of a commercial probiotic cheese containing Lactobacillus rhamnosus HN001 and Lactobacillus acidophilus NCFM on the nutritional modulation of immune parameters in older volunteers (70+). These would also serve as a model for immune compromised subjects. The aim of the current study was to determine whether specific probiotic bacteria in a cheese matrix would have immune-enhancing effects on healthy older individuals in a nursing home setting, similar to those reported earlier (Gill et al., 2000; Gill et al., 2001; Sanders & Klaenhammer, 2001). Elderly subjects without acute illness, 21 women and 10 men, age range from 72 to 103 (median, 86), residing in a nursing home for older individuals were recruited for this study (Table 1). The baseline data regarding the prevalence of disease and the use of medications are shown in Fig. 1. Dementia and cardiovascular disease were the most common conditions, while aspirin, diuretics, and calcium/vitamin D intake were the most frequent.

New Delhi metallo-β-lactamase 1 was

New Delhi metallo-β-lactamase 1 was selleck chemicals llc searched for using specific primers [13]. PMQR genes qnrA, qnrB, qnrC, qnrD, qnrS, qepA and aac(6′)-Ib-cr were investigated by PCR as previously described [5]. Identity of the β-lactamase and quinolone resistance genes was confirmed by DNA sequence analysis. Twenty-seven of the 31 isolates for which information was available were from adult and four from pediatric cases. All but one patient were hospitalized and 24 were receiving imipenem treatment. There was only one instance

of two isolates with different susceptibility patterns from the same patient. A high proportion of isolates was from fecal samples (14/31), followed by exudates and blood (6 and 5, respectively) and other normally sterile sites. All isolates were confirmed by E-test to be resistant to cefotaxime and/or ceftazidime. Only one isolate was resistant to carbapenems. Fourteen and 24 isolates were resistant to gentamicin and ciprofloxacin, respectively. The E. coli isolates were unevenly distributed into the four phylogenetic groups,

23 belonging to group D, 7 to A and 1 each to B1 and B2 (Table 1). Consistent with previous reports from Egypt and other low-resource countries, phylogroups A and D were predominant, whereas the hyperepidemic strain B2-ST131 was under-represented [8]. Rep-PCR fingerprinting enabled the identification of four clusters, including 15 phylogroup D isolates,

buy PLX3397 and 17 single patterns (Fig. 1). This suggests that the observed over-representation of phylogroup D might be at least buy Paclitaxel partially explained by intra-hospital cross-transmission. In contrast, the heterogeneity of group A isolates which, along with group B1, are reportedly frequently associated with commensal organisms, suggests a prominent epidemiological role for this phylogroup in the region under study. According to MLST one cluster belonged to ST405 and the remaining three to ST68. All but one of the non-clustered phylogroup D isolates were also attributed with ST68. Isolates D/ST405 have been repeatedly reported to express a multiresistant phenotype [2, 8]. In contrast, isolates D/ST68 carrying blaCTX-M-15 and aac(6′)-Ib-cr were an unexpected finding. Indeed, only two D/ST68 isolates containing blaCMY-2 have been reported recently, both from wild coastline birds in Miami Beach, Florida, USA [14]. The B2 strain belongs to the worldwide spread ST131 [2]. All but one isolate in cluster 1 and 13 non clustered isolates showed a blaCTX-M-15 gene, which was consistent with the global predominance of this ESBL [2]. SHV-12 and CMY-2 were detected in only four and three non-clustered isolates, respectively. Three isolates co-produced OXA-48 and/or VIM carbapenemases (Table 1). Although carbapenemases have been infrequently detected in E.

Results obtained from three independent experiments showed

Results obtained from three independent experiments showed

that although Treg cells from uninfected animals are able to suppress proliferation at various degrees (36.1–85.7%), Treg cells from infected mice induced a significantly higher suppression of target cells proliferation (84.3–97.4%); as expected, Treg cells alone were unable to proliferate under these conditions. These results demonstrate that during infection, the residual activated Treg cells display an increased suppressive capacity. The activated phenotype and the increased suppression capacity of the residual Treg cells could explain the apparent discrepancy between the immunosuppression and the reduced proportion of Treg cells observed during infection. In a first attempt to evaluate the role of Treg cells in the observed immunosuppression, we injected animals with anti-CD25 mAb and examined whether proliferation was recovered. However, as we previously reported, treatment of C57BL/6J mice with anti-CD25 mAb before infection eliminates mainly activated cells, and thus the role of Treg cells is impossible to elucidate using this approach 38. Thus, we used Foxp3EGFP mice to directly

assess whether Treg cells mediate immunosuppression. Foxp3+ cells were eliminated by cell sorting (Fig. 4A) and proliferation of Foxp3− cells was analysed (Fig. 4B). As expected, proliferation of ungated, CD4+ and CD8+ lymphocytes was suppressed when unsorted splenocytes were assayed. These results are indistinguishable

from those shown in Fig. 1, demonstrating that the EGFP+ phenotype does not alter the Ku-0059436 datasheet immunosuppression pattern of T. gondii-infected mice. When Foxp3+ cells were eliminated from infected mice splenocytes, a proliferation recovery was clearly observed in the ungated population. CD4+ cells showed a strong proliferation, similar to that observed in cells from uninfected mice. CD8+ Casein kinase 1 cells from infected animals also recovered their proliferative response. Elimination of Foxp3+ cells from uninfected mice did not alter proliferation of CD4+ nor CD8+ cells. Statistical analysis of the data collected from two independent experiments confirmed that after Treg-cell removal the percentage of divided CD4+ cells from infected mice was significantly enhanced and was similar to that of cells from uninfected animals (Fig. 4C); a non-significant increase in the percentage of divided cells from the ungated and CD8+ subsets was observed. Since the percentage of divided cells only represents the proportion of the original population that responded by dividing 39 we also calculated the percentage of proliferating cells (cells found in any round of division). Figure 4D shows that when Treg cells are eliminated, the percentages of proliferating CD4+ and CD8+ cells are similar for uninfected and infected animals.

4B); however, NK cells from 4T1/IL-1β-tumor-bearing mice expresse

4B); however, NK cells from 4T1/IL-1β-tumor-bearing mice expressed 5–10 times less CD27 protein than NK cells from the other mice (Fig. 4B). Moreover, the tumor-bearing mice contained less CD11b+ NK cells in the bone marrow (Fig. 4A (right) and B) indicating a block in the differentiation of NK cells in these mice. In contrast to the BM, the total number of splenic NK cells was five-fold

increased in both groups of tumor-bearing mice (Fig. 4A). More importantly, CD11b+ and KLRG-1+ cells were absent from 4T1/IL-1β-tumor-bearing mice, while splenic NK cells from 4T1-tumor-bearing mice expressed CD11b and KLRG1 at levels and frequencies comparable to naïve mice (Fig. 4B and C). Further analyses showed a rapid down-modulation of NKG2D but not NKp46 expression by NK cells after injection of 4T1- and 4T1/IL-1β-tumor cells. The reduced expression of NKG2D occurred earlier and was more pronounced Z-VAD-FMK clinical trial in 4T1/IL-1β- than in 4T1-tumor bearing mice (Fig. 5A and data not shown). To explore whether the MDSC subsets were involved in the reduction of NKG2D expression by NK cells, we sorted Ly6Clow MDSC and Ly6Cneg MDSC from the spleens of 4T1- or 4T1/IL-1β-tumor-bearing mice,

respectively, and co-cultured them for 24 h with selleck kinase inhibitor splenocytes from naïve Rag2−/− mice in the presence of IL-2. We observed a stronger reduction of NKG2D expression by Rag2−/− NK cells when co-cultured with Ly6Cneg MDSC as compared with Ly6Clow MDSC (Fig. 5B, top). Furthermore, transwell experiments revealed GNAT2 that NKG2D downregulation was cell–cell contact dependent (Fig. 5B, middle). We obtained similar results in vivo after adoptive transfer of purified Ly6Cneg MDSC and Ly6Clow MDSC, respectively,

into naïve Rag2−/− mice. NK cells from Rag2−/− mice given Ly6Cneg MDSC displayed reduced expression of NKG2D 2 days after transfer, while NKG2D levels remained unchanged on NK cells from mice transplanted with Ly6Clow MDSC (Fig. 5B, bottom). Together, these results indicated that MDSC subsets induce the downregulation of NKG2D on the cell surface of NK cells and that Ly6Cneg MDSC were more potent in this process in vitro and in vivo. We next addressed whether the down modulation of NKG2D expression was associated with functional impairment of NK cells in vivo. We adoptively transferred enriched MDSC isolated from BM and spleen of 4T1- or 4T1/IL-1β-tumor-bearing mice, respectively, intravenously into naïve BALB/c mice and challenged them 2–3 days later with luciferase-expressing YAC-1 target cells (Luc-YAC-1). As few as 7–8 h thereafter, NK cell activity was significantly lower in mice that had received MDSC from the BM and spleen of 4T1/IL-1β-tumor-bearing mice as compared to those having received MDSC from 4T1-tumor-bearing mice or Gr-1+CD11b+ cells from naive mice (Fig. 5C). There was no clearance of Luc-YAC-1 cells in NK-deficient Rag2−/−IL-2Rβ−/− mice within the 8-h period confirming NK cells as the effectors (Supporting Information Fig. 5).

These results indicate that, in the mouse brain, the R(G 242/255/

These results indicate that, in the mouse brain, the R(G 242/255/268) strain spread more Selleck PLX4032 efficiently than did the RC-HL strain. Some studies have demonstrated

an inverse correlation between pathogenicity and apoptosis induced by G protein (9, 21, 22). We thought that infection with the RC-HL strain would induce apoptosis more strongly than would infection with the R(G 242/255/268) strain. Using TUNEL staining, we compared induction of apoptosis in NA cells infected with RC-HL strain with that in NA cells infected with the R(G 242/255/268) strain (Fig. 3a). We carried out TUNEL staining in NA cells infected with each strain (MOI = 2) at 48 hpi and determined the percentage of TUNEL-positive cells in the infected cells. The percentage of TUNEL-positive cells was modestly increased by infection with the RC-HL or R(G 242/255/268) strain, indicating that infection with these strains induces apoptosis in NA cells. Notably, there was no clear difference BGJ398 concentration between the percentages of TUNEL-positive cells in RC-HL and R(G 242/255/268) strain-infected cells. Next, we compared induction of apoptosis in mouse brains infected with RC-HL strain with that in mouse brains infected with R(G 242/255/268) strain

by using TUNEL staining (Fig. 3b). It was found that infections with both strains moderately induced apoptosis in the hippocampal area of the infected mouse brain (Fig. 3b, left), where both strains propagated efficiently (Fig. 3b, right). Importantly, no clear difference in the numbers of TUNEL-positive apoptotic

cells was observed Glutamate dehydrogenase in the brains infected with these strains, consistent with the results in NA cells. It has been reported that there is a positive correlation between apoptosis-inducing ability of rabies virus and degree of expression of G protein (9, 21, 23). Thus, we investigated degree of expression of each viral G protein in cell culture by using ELISA with several monoclonal antibodies against G protein, which recognize different antigenic sites (20) (Fig. 4). The results showed that degree of expression of G protein did not differ in RC-HL strain- and R(G 242/255/268) strain-infected cells, supporting the finding that there is no difference in the apoptosis-inducing abilities of these strains. We compared the multi-step growth curves of RC-HL and R(G 242/255/268) strains in NA cells (Fig. 5a). The growth curve of the R(G 242/255/268) strain was almost the same as that of the RC-HL strain, and virus titers of both strains in the culture fluid reached 108 FFU/ml by 5 dpi. Some studies have demonstrated that internalization of rabies virus into cells is an important factor for viral pathogenicity (13, 24, 25). Therefore, we also compared the efficiencies of virus internalization of RC-HL and R(G 242/255/268) strains by using NA cells (Fig. 5b).

Results from GWAS have the potential to be translated in biologic

Results from GWAS have the potential to be translated in biological knowledge and, hopefully, clinical application. There are a number of immune pathways highlighted in GWAS that may have therapeutic implications in PBC and in other autoimmune diseases, such as the anti-interleukin-12/interleukin-23, nuclear factor-kb, tumor necrosis factor, phosphatidylinositol LY2157299 order signaling

and hedgehog signaling pathways. Further areas in which GWAS findings are leading to clinical applications either in PBC or in other autoimmune conditions, include disease classification, risk prediction and drug development. In this review we outline the possible next steps that may help accelerate progress from genetic studies to the biological knowledge that would guide the development of predictive, preventive, or therapeutic measures in PBC. Primary

biliary cirrhosis (PBC) click here is the most common autoimmune liver disease and is considered a model of organ-specific autoimmune diseases [1]. It is characterized by loss of tolerance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients, the development of fibrosis and cirrhosis. Patients with PBC may present with symptoms as fatigue, pruritus and/or jaundice, but the majority of them are asymptomatic at diagnosis. Glutamate dehydrogenase A diagnosis of PBC can be made with confidence in adult patients with otherwise unexplained elevation of alkaline phosphatase and presence of antimitochondrial antibodies (AMAs) at a titre of ≥1:40 and/or AMA type M2. A liver biopsy is not essential for the diagnosis of PBC in these patients, but allows activity and stage of the disease to be assessed. Progression of disease in PBC is variable with a substantial proportion of patients eventually developing cirrhosis and liver failure. The only licensed therapy for PBC is ursodeoxycholic acid (UDCA) which has been demonstrated to exert anticholestatic

effects in various cholestatic disorders. Several potential mechanisms and sites of action of UDCA have been unraveled in clinical and experimental studies which might explain its beneficial effects. These include protection of injured cholangiocytes against the toxic effects of bile acids, particularly at an early stage; stimulation of impaired hepatocellular secretion by mainly posttranscriptional mechanisms, including stimulation of synthesis, targeting and apical membrane insertion of key transporters, more relevant in the advanced cholestasis; stimulation of ductular alkaline choleresis and inhibition of bile acid-induced hepatocyte and cholangiocyte apoptosis.

These can be further subdivided into B1a and B1b, where the major

These can be further subdivided into B1a and B1b, where the majority of B1a B cells stem from the fetal liver, and the B2 cells into follicular (FO) and marginal zone (MZ) B cells. B1 and MZ B cells are a source of natural antibodies and respond to T cell–independent (Ti) antigens. The dominating subset in blood, spleen and lymph nodes is FO

B cells that mainly respond to T cell–dependent (Td) antigens. After the B cells become activated, they can differentiate into memory cells and/or antibody-secreting plasma cells. Upon activation, FO B cells together with follicular dendritic cells (FDCs) and follicular T helper (TFH) cells form germinal centres (GC), secondary structures that are located within B cell follicles [2, 3]. FDCs trap and retain antigen on their surface in the form of immune complexes [4], and TFH cells have been found to provide the B cell with differentiation signals via cognate interactions [5-8]. GCs also support BCR modifications, that is, class switch recombination (CSR) and somatic hypermutation (SHM), processes that require the activation induced deaminase (AID) enzyme [9]. The GC can be divided into two zones, a dark zone where B cells undergo clonal expansion and a light zone where B cells undergo selection based on their ability to interact with FDCs and T helper

cells [3, 10, 11]. As B cells leave the GCs, they differentiate into either memory B cells or antibody-producing plasma cells, expressing BCRs that may have undergone affinity maturation due to SHM and/or a change in effector function as a result of CSR. In humans, selleck screening library the proportion of memory B cells is much higher than that in mice, at least those kept under specific pathogen-free conditions, and human memory B cells have been predominantly characterized as cells expressing CD27, a marker for antigen-experienced cells [12]. Among human CD27+ B cells, there exist both IgM and isotype-switched cells that have undergone SHM [12, 13]. In addition, memory B cells

that lack expression of CD27 have been described [14]. The observation that CD27 is not an appropriate marker for memory B cells in mice [15, 16], and due to the paucity of memory B cells [17, 18], it has been technically difficult Oxymatrine to carefully study these. To circumvent this problem, many studies have relied on the use of hybridomas and transgenic (TG) mice expressing a particular antibody H chain, either alone or in combination with a defined L chain, resulting in a high frequency of B cells expressing a BCR with a predefined antigen specificity. Introduction of such constructs into the Ig H (and L) chain locus (knock-in) also allows CSR and hence the possibility to study B cells expressing isotype-switched antigen-specific BCRs. Classically, memory B cells have been defined as progenies of GC B cells expressing isotype-switched and substantially mutated BCRs.

Nephrectomy did not affect the incidence of hypertension, but an

Nephrectomy did not affect the incidence of hypertension, but an increase in systolic BP (2.4 mmHg, P > 0.05) was observed, which increased further with follow up (1.1 mmHg/decade). Diastolic BP increased after nephrectomy (3.1 mmHg), but this increment did not change with duration of follow up.26 Another large meta-analysis by Boudville et al.27 examined results from 48 studies with a total of 5145 donors (Fig. 1). They concluded that kidney donors have an increase in BP of approximately 5 mmHg systolic and 4 mmHg diastolic, above that expected

with normal ageing, within 5–10 years of donation. In the general population, every 10 mmHg increase in systolic BP and 5 mmHg increase in diastolic BP is associated with a 1.5-fold increase in mortality from both ischaemic heart disease and stroke.28 Boudville et al.27 also reviewed the risk of developing hypertension in donors. Six studies were assessed (total of 249 donors comparing results against 161 control participants), however, results could not be pooled due to heterogeneity in the groups. Only one of the six studies (Watnick et al.20) showed an increase in the risk of developing hypertension (relative risk: 1.9 (confidence interval: 1.1–3.5)). All others showed no difference. It must be noted that none of these studies were adequately powered to detect a meaningful

difference between the study and the control groups (less than 80% chance of detecting a 1.5-fold increase Mephenoxalone in the GSK2126458 order risk of hypertension). The donor population in each individual study ranged from 15 to 50 patients whereas the control population ranged from only 0 to 10 patients. In summary, there is no conclusive evidence that kidney donation increases the risk of developing hypertension in normal individuals. The studies examining this, however, are very limited. Studies do show that kidney donation is associated with a small increase in BP within the normal range. Since reduced glomerular filtration rate (GFR) and hypertension are both important cardiovascular risk factors, it is very important to explain

this potential added risk and also aggressively treat other cardiovascular risk factors such as smoking, hyperlipidaemia, obesity, metabolic syndrome and diabetes during follow up. The presence of established hypertension in potential live kidney donors has been considered to be a contraindication to proceeding with donation. Conclusive recommendations regarding the routine use of hypertensive donors cannot be made at this stage since only short-term cohort studies have been reported. Textor et al.29 showed that 58 donors with normal renal function and controlled hypertension on 1–2 medications showed no increased risk of renal deterioration, microalbuminuria or poor BP control at 12 months. A follow-up study by the same investigators examined 148 living kidney donors before and 6–12 months after nephrectomy.

[125, 126] Since activation of sulphatide reactive type II NKT ce

[125, 126] Since activation of sulphatide reactive type II NKT cells inhibits the effector functions of pathogenic conventional Th1/Th17 cells in peripheral organs VX-809 in vivo as well as in affected tissues such as the CNS and liver, the targeting of these cells leads to a broader therapeutic response than the targeting of type I NKT cells alone for intervention in autoimmune disease. Although some studies suggest that

type I NKT cells may cross-regulate type II NKT cell activity,[127] additional studies are needed to clarify the mechanisms of regulation involved. It is clear that activation of type I NKT cells with αGalCer leads to a cascade of events that modulates the activity of several cell types, including DCs, B cells, NK cells and neutrophils.[2, 3, 128] It is likely that sulphatide-mediated induction of anergy in type

I NKT cells also modulates the activity of these other cell types. As mentioned above, our data clearly indicate a significant alteration in the activity of DC populations following sulphatide-mediated activation of type II NKT cells. Current studies are investigating the roles of other cell types that are stimulated after type II NKT cell activation in the presence and absence buy Tamoxifen of type I NKT cells. Immune regulatory activity of NKT cells can be mediated by the cytokines secreted by NKT cells themselves or following their interaction with other immune cells, including DCs, Treg cells, monocytes and B cells. Hence, activation of NKT cell subsets can result in the deviation of a cytokine secretion profile in MHC-restricted CD4+ T cells

Anidulafungin (LY303366) towards either a pronounced Th1- or Th2-like response. Generally, for experimental diseases in which Th1 or Th17 cells mediate pathology, immune deviation of the pathogenic T-cell response towards a Th2-like phenotype following type I NKT cell activation with αGalCer or its analogues is protective from disease. For example, protection from type 1 diabetes by NKT cells is associated with an elevated Th2 cytokine profile in pathogenic islet protein-reactive CD4+ T cells,[4, 129, 130] whereas a Th1 bias correlates with disease severity.[3, 109] In spite of this finding, a Th1 to Th2 cytokine profile shift in conventional CD4+ T cells alone may not be sufficient to prevent type 1 diabetes in NOD mice[71, 131] or EAE in susceptible mice.[19, 98, 109-112] Analyses of cytokine profiles secreted by both activated NKT cells and different APCs after their encounters in vivo will also expand our growing knowledge of the mechanisms of leucocyte communication, as described above.

rodentium stimulation [9] The different results may depend on th

rodentium stimulation [9]. The different results may depend on the assay employed (microscopy versus immunoblot), the type of cells (primary versus immortalized macrophages) or the bacteria used. Further studies are needed to clarify whether ASC speck formation and oligomerization

are essential for noncanonical inflammasome signaling. While it is unclear how caspase-11 interacts with the inflammasome components to support IL-1β and IL-18 release, caspase-11 circumvents the requirement for NLRP3 for the production of IL-1α [3]. Indeed, IL-1α selleck products release was suppressed in Casp11−/− or in double Casp1−/− Casp11−/− macrophages, but not in Nlrp3−/− or Asc−/− macrophages, upon noncanonical stimuli (CTB, E. coli) (Table 1).

As caspase-11 activation depends on the TRIF/IFNs pathway, similar to IL-1β, IL-1α release was severely impaired in Trif−/−, Irf3−/−, Ifnra1−/−, Stat1−/−, and Irf9−/− macrophages stimulated with EHEC or C. rodentium [9]. However, IL-1α remains fully dependent on caspase-1 when canonical stimuli (ATP, C. difficile toxin B) are employed [3]. Many of the studies discussed so far have relied upon in vitro experiments to elucidate the roles of inflammasome pathway molecules, but the real importance of these interactions becomes apparent in in vivo models of human disease. In a mouse model of acute septic shock induced by LPS, serum IL-1β and IL-18 levels were markedly reduced in Casp11−/−, double Casp1−/− Casp11−/− and Casp1−/− Casp11Tg animals click here [3]. IL-1α serum levels were similarly low in mice lacking caspase-11 (Casp11−/−, double Casp1−/− Casp11−/−), but in contrast were unaffected in Casp1−/− Casp11Tg mice. These results confirm that both caspase-1 and caspase-11 are necessary for IL-1β/IL-18

release, whereas IL-1α production is fully dependent on caspase-11. Canonical activation of caspase-1 by NLRP3 and NLRC4 inflammasomes induces a form of programmed GPX6 cell death known as pyroptosis, a genetically regulated form of cell death that acts as an innate immune effector mechanism against intracellular bacteria [19]. Therefore, attention turned to the potential role of the caspase-11-mediated noncanonical inflammasome activation pathway in this mechanism of cell death. Early studies showed that caspase-11 was upregulated during cell death and that its overexpression per se induced cell death [5, 7]. Consequently, cell survival was markedly increased in spleens from Casp11−/− mice injected with LPS compared with wild-type controls [7]. Caspase-11 directly controls the activation of the effector caspases 3 and 7 of the apoptotic pathway independent of caspase-1 [7]. Recently it was shown that caspase-11, but not caspase-1, NLRC4 or ASC, was responsible for cell lethality in macrophages following application of noncanonical stimuli (Table 1) [3, 10, 20].