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1.  ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells 
The Journal of Clinical Investigation  null;126(10):3905-3916.
Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle. Moreover, in histone 2B-GFP mice, the 2B-GFP label was retained in Tsp cells, indicative of a slow-cycling phenotype. Human Tsp cells displayed a distinct gene-expression profile that was enriched for genes overexpressed in Trm cells. In mice, proteins encoded by Tsp signature genes, including nuclear receptor subfamily 4 group A member 1 (NR4A1) and ATP-binding cassette (ABC) transporters, influenced the function and differentiation of Trm cells. Responses to adoptive transfer of human Tsp cells into immune-deficient mice and plerixafor therapy suggested that human Tsp cell mobilization could be manipulated as a potential cellular therapy. These data identify a distinct subset of human T cells with a quiescent/slow-cycling phenotype, propensity for tissue enrichment, and potential to mobilize into circulation, which may be harnessed for adoptive cellular therapy.
doi:10.1172/JCI85329
PMCID: PMC5096804  PMID: 27617863
2.  Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset 
The Journal of Experimental Medicine  2016;213(7):1223-1239.
Streptozotocin causes T1D by inducing the translocation of intestinal bacteria into pancreatic lymph nodes and driving the development of pathogenic Th1 and Th17 cells through NOD2 receptor.
Type 1 diabetes (T1D) is an autoimmune disease that is triggered by both genetic and environmental factors, resulting in the destruction of pancreatic β cells. The disruption of the intestinal epithelial barrier and consequent escape of microbial products may be one of these environmental triggers. However, the immune receptors that are activated in this context remain elusive. We show here that during streptozotocin (STZ)-induced T1D, the nucleotide-binding oligomerization domain containing 2 (NOD2), but not NOD1, participates in the pathogenesis of the disease by inducing T helper 1 (Th1) and Th17 cells in the pancreatic LNs (PLNs) and pancreas. Additionally, STZ-injected wild-type (WT) diabetic mice displayed an altered gut microbiota compared with vehicle-injected WT mice, together with the translocation of bacteria to the PLNs. Interestingly, WT mice treated with broad-spectrum antibiotics (Abx) were fully protected from STZ-induced T1D, which correlated with the abrogation of bacterial translocation to the PLNs. Notably, when Abx-treated STZ-injected WT mice received the NOD2 ligand muramyl dipeptide, both hyperglycemia and the proinflammatory immune response were restored. Our results demonstrate that the recognition of bacterial products by NOD2 inside the PLNs contributes to T1D development, establishing a new putative target for intervention during the early stages of the disease.
doi:10.1084/jem.20150744
PMCID: PMC4925011  PMID: 27325889
3.  Inflammasomes 
Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1β and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease.
In response to infection or stress, inflammasomes assemble in the cytosol and activate caspase-1-mediated inflammatory responses. They have also been implicated in various diseases (e.g., gout).
doi:10.1101/cshperspect.a016287
PMCID: PMC4292152  PMID: 25324215
4.  Peripherally induced tolerance depends on pTreg cells that require Hopx to inhibit intrinsic IL-2 expression 
Dendritic Cells (DCs) can induce peripheral immune tolerance that prevents autoimmune responses. Antigen presentation by peripheral DCs under steady state conditions leads to a conversion of some peripheral CD4+ T cells into Treg cells that require Homeodomain Only Protein (Hopx) to mediate T cell unresponsiveness. However, the roles of these peripheral (p)Treg cells in averting autoimmune responses as well as immunological mechanisms of Hopx remain unknown. Here we report that Hopx+ pTreg cells converted by DCs from Hopxneg T cells are indispensible to sustain tolerance that prevents autoimmune responses directed at self-antigens during experimental acute encephalomyelitis (EAE). Our studies further reveal that Hopx inhibits intrinsic IL-2 expression in pTreg cells after antigenic re-challenge. In the absence of Hopx, increased levels of IL-2 lead to death and decreased numbers of pTreg cells. Therefore formation of Hopx+ pTreg cells represents a crucial pathway of sustained tolerance induced by peripheral DCs and the maintenance of such pTreg cells and tolerance requires functions of Hopx to block intrinsic IL-2 production in pTreg cells.
doi:10.4049/jimmunol.1500174
PMCID: PMC4530038  PMID: 26170384
5.  Immune-microbiota interactions in health and disease 
Clinical immunology (Orlando, Fla.)  2015;159(2):122-127.
Recent studies have revealed that the intestinal microbiota plays an important role in host physiology and pathophysiology in health and disease. One of the major mechanisms by which the gut microbiota influences the host is through its interactions with and effects on the host immune system. In this review, we discuss the reciprocal interactions between the host immune system and the gut microbiota, with a particular focus on individual microbes that impact the host through dramatic and specific interactions with the adaptive immune system. We highlight the idea that the presence or absence of specific immunologically important members of the microbiota can determine disease susceptibility and propose that the identification and characterization of these bacteria in humans will eventually allow us to elucidate the role of microbiota composition in human disease.
doi:10.1016/j.clim.2015.05.014
PMCID: PMC4943041  PMID: 26141651
6.  Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis 
Cell  2015;163(6):1444-1456.
SUMMARY
The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease Ulcerative Colitis. Here we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp−/−;Il18rΔ/EC mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction which underlies the pathology of Ulcerative Colitis.
doi:10.1016/j.cell.2015.10.072
PMCID: PMC4943028  PMID: 26638073
7.  The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity 
Science (New York, N.Y.)  2016;352(6281):99-103.
Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded by Tyro3 in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell–specific Pros1 knockouts phenocopied the loss of Tyro3. Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.
doi:10.1126/science.aaf1358
PMCID: PMC4935984  PMID: 27034374
8.  Nlrp6 regulates intestinal antiviral innate immunity 
Science (New York, N.Y.)  2015;350(6262):826-830.
The nucleotide-binding oligomerization domain-like receptor (Nlrp) 6 maintains gut microbiota homeostasis and regulates antibacterial immunity. We now report a role for Nlrp6 in the control of enteric virus infection. Nlrp6−/− and control mice systemically challenged with encephalomyocarditis virus had similar mortality, however, the gastrointestinal tract of Nlrp6−/− mice exhibited increased viral loads. Nlrp6−/− mice orally infected with encephalomyocarditis virus had increased mortality and viremia compared to controls. Similar results were observed with murine norovirus 1. Nlrp6 bound viral RNA via the RNA helicase Dhx15 and interacted with Mavs to induce type I/III interferons (IFNs) and IFN-stimulated genes (ISGs). These data demonstrate that Nlrp6 functions with Dhx15 as a viral RNA sensor to induce ISGs, and this effect is especially important in the intestinal tract.
doi:10.1126/science.aab3145
PMCID: PMC4927078  PMID: 26494172
9.  Guanylate Binding Proteins Enable Rapid Activation of Canonical and Noncanonical Inflammasomes in Chlamydia-Infected Macrophages 
Infection and Immunity  2015;83(12):4740-4749.
Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate cell-autonomous host resistance to bacterial pathogens and promote inflammasome activation. The prevailing model postulates that these two GBP-controlled activities are directly linked through GBP-dependent vacuolar lysis. It was proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed the microbial refuge and simultaneously contaminated the host cell cytosol with microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated host resistance and GBP-mediated inflammatory responses can be uncoupled. We show that PVs formed by the rodent pathogen Chlamydia muridarum, so-called inclusions, remain free of GBPs and that C. muridarum is impervious to GBP-mediated restrictions on bacterial growth. Although GBPs neither bind to C. muridarum inclusions nor restrict C. muridarum growth, we find that GBPs promote inflammasome activation in C. muridarum-infected macrophages. We demonstrate that C. muridarum infections induce GBP-dependent pyroptosis through both caspase-11-dependent noncanonical and caspase-1-dependent canonical inflammasomes. Among canonical inflammasomes, we find that C. muridarum and the human pathogen Chlamydia trachomatis activate not only NLRP3 but also AIM2. Our data show that GBPs support fast-kinetics processing and secretion of interleukin-1β (IL-1β) and IL-18 by the NLRP3 inflammasome but are dispensable for the secretion of the same cytokines at later times postinfection. Because IFN-γ fails to induce IL-1β transcription, GBP-dependent fast-kinetics inflammasome activation can drive the preferential processing of constitutively expressed IL-18 in IFN-γ-primed macrophages in the absence of prior Toll-like receptor stimulation. Together, our results reveal that GBPs control the kinetics of inflammasome activation and thereby shape macrophage responses to Chlamydia infections.
doi:10.1128/IAI.00856-15
PMCID: PMC4645370  PMID: 26416908
10.  Making plant science purposeful and relevant to all 
Journal of Experimental Botany  2016;67(11):3186-3187.
doi:10.1093/jxb/erw201
PMCID: PMC4892746  PMID: 27241492
Genome-wide association study (GWAS); GMO; investment; investors; new technologies; roadmap; society.
11.  Recent advances in dynamic m6A RNA modification 
Open Biology  2016;6(4):160003.
The identification of m6A demethylases and high-throughput sequencing analysis of methylated transcriptome corroborated m6A RNA epigenetic modification as a dynamic regulation process, and reignited its investigation in the past few years. Many basic concepts of cytogenetics have been revolutionized by the growing understanding of the fundamental role of m6A in RNA splicing, degradation and translation. In this review, we summarize typical features of methylated transcriptome in mammals, and highlight the ‘writers’, ‘erasers’ and ‘readers’ of m6A RNA modification. Moreover, we emphasize recent advances of biological functions of m6A and conceive the possible roles of m6A in the regulation of immune response and related diseases.
doi:10.1098/rsob.160003
PMCID: PMC4852458  PMID: 27249342
m6A; mRNA; methylation
12.  A Molecular Chipper technology for CRISPR sgRNA library generation and functional mapping of noncoding regions 
Nature Communications  2016;7:11178.
Clustered regularly-interspaced palindromic repeats (CRISPR)-based genetic screens using single-guide-RNA (sgRNA) libraries have proven powerful to identify genetic regulators. Applying CRISPR screens to interrogate functional elements in noncoding regions requires generating sgRNA libraries that are densely covering, and ideally inexpensive, easy to implement and flexible for customization. Here we present a Molecular Chipper technology for generating dense sgRNA libraries for genomic regions of interest, and a proof-of-principle screen that identifies novel cis-regulatory domains for miR-142 biogenesis. The Molecular Chipper approach utilizes a combination of random fragmentation and a type III restriction enzyme to derive a densely covering sgRNA library from input DNA. Applying this approach to 17 microRNAs and their flanking regions and with a reporter for miR-142 activity, we identify both the pre-miR-142 region and two previously unrecognized cis-domains important for miR-142 biogenesis, with the latter regulating miR-142 processing. This strategy will be useful for identifying functional noncoding elements in mammalian genomes.
The interrogation of noncoding regions of the genome with CRISPR strategies requires dense and, ideally, inexpensive libraries to ensure coverage and customisation. Here the authors present 'Molecular Chipper' that uses fragmentation to generate guide RNAs from input DNA.
doi:10.1038/ncomms11178
PMCID: PMC4820989  PMID: 27025950
13.  Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants 
Nature  2008;453(7198):1122-1126.
Aluminium adjuvants, typically referred to as ‘alum’, are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system1,2. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1β and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund’s adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.
doi:10.1038/nature06939
PMCID: PMC4804622  PMID: 18496530
14.  Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress 
eLife  null;5:e10031.
The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.
DOI: http://dx.doi.org/10.7554/eLife.10031.001
eLife digest
Consuming the right amount of food is important for health. Eating too little for a long time causes damage to organs, and overeating can cause harm as well, in the form of conditions such as obesity and type 2 diabetes. Several signaling molecules and brain regions are linked to controlling food consumption and ensuring the body receives the correct amount of nutrients to fuel its activities.
Previous studies have found that two proteins called JNK1 and JNK2, which are found in most tissues of the body, can reduce how much energy cells use. This can trigger insulin resistance and fat accumulation, and so suggests that blocking the activity of these proteins may help to treat type 2 diabetes and obesity. However, the role of another JNK protein – JNK3, which is mostly found in the brain – was not known.
Now, Vernia, Morel et al. have investigated the role of JNK3 in metabolism. It was found that JNK3 reduced the amount of food consumed by mice provided with a cafeteria (high fat) diet. Mice that lacked JNK3 ate far more food and gained more weight on a high fat diet than normal mice. However, JNK3 played no role in food consumption when mice were fed a standard chow diet. Treating normal mice with leptin – an appetite-suppressing hormone – caused them to lose weight, but did not affect mice that lacked JNK3.
Examining the brains of the mice revealed that in normal mice, JNK3 in a specific sub-population of neurons decreases the production of proteins that promote eating. However, the proteins continued to be produced in mice that lacked JNK3, encouraging overeating.
Overall, the results suggest that blocking the activity of all the JNK proteins will not help treat obesity and diabetes as shutting down JNK3 could encourage overeating. Therefore, future investigation into treatments for these conditions should focus on drugs that specifically target JNK1 and JNK2, and not JNK3.
DOI: http://dx.doi.org/10.7554/eLife.10031.002
doi:10.7554/eLife.10031
PMCID: PMC4798947  PMID: 26910012
signal transduction; JNK; leptin; satiety; Mouse
15.  YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity 
Nature Communications  2016;7:10789.
Regulatory T (Treg) cells are essential for maintenance of immune homeostasis. Foxp3 is the key transcription factor for Treg-cell differentiation and function; however, molecular mechanisms for its negative regulation are poorly understood. Here we show that YY1 expression is lower in Treg cells than Tconv cells, and its overexpression causes a marked reduction of Foxp3 expression and abrogation of suppressive function of Treg cells. YY1 is increased in Treg cells under inflammatory conditions with concomitant decrease of suppressor activity in dextran sulfate-induced colitis model. YY1 inhibits Smad3/4 binding to and chromatin remodelling of the Foxp3 locus. In addition, YY1 interrupts Foxp3-dependent target gene expression by physically interacting with Foxp3 and by directly binding to the Foxp3 target genes. Thus, YY1 inhibits differentiation and function of Treg cells by blocking Foxp3.
Treg control the magnitude of immune responses, but how these cells are controlled is less understood. Here the authors show that a transcriptional repressor YY1 inhibits Foxp3, the master regulator of Treg, by repressing its transcription, and by directly interacting with Foxp3 and its target gene promoters.
doi:10.1038/ncomms10789
PMCID: PMC4762897  PMID: 26892542
16.  IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury 
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. While previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. Recently, toll-like receptor (TLR) signaling has been identified as a regulator of pulmonary fibrosis. Interleukin-1 receptor-associated kinase-M (IRAK-M), a MyD88-dependent inhibitor of TLR signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient in IRAK-M (IRAK-M−/−) were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with reduced production of interleukin (IL)-13 compared to wild type (WT) control mice. Bone marrow (BM) chimera experiments indicated that IRAK-M expression by BM derived cells, rather than structural cells, promoted fibrosis. After bleomycin, WT macrophages displayed an alternatively activated phenotype, whereas IRAK-M−/− macrophages displayed higher expression of classically activated macrophage markers. Using an in vitro co-culture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M−/−, mice promoted increased collagen and α-smooth muscle actin expression from lung fibroblasts in an IL-13-dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from IPF patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages towards an alternatively activated profibrotic phenotype, which promotes collagen production leading to the progression of experimental pulmonary fibrosis.
doi:10.4049/jimmunol.1402377
PMCID: PMC4384172  PMID: 25595781
17.  T Cell Receptor Mediated Calcium Entry Requires Alternatively Spliced Cav1.1 Channels 
PLoS ONE  2016;11(1):e0147379.
The process of calcium entry in T cells is a multichannel and multi-step process. We have studied the requirement for L-type calcium channels (Cav1.1) α1S subunits during calcium entry after TCR stimulation. High expression levels of Cav1.1 channels were detected in activated T cells. Sequencing and cloning of Cav1.1 channel cDNA from T cells revealed that a single splice variant is expressed. This variant lacks exon 29, which encodes the linker region adjacent to the voltage sensor, but contains five new N-terminal exons that substitute for exons 1 and 2, which are found in the Cav1.1 muscle counterpart. Overexpression studies using cloned T cell Cav1.1 in 293HEK cells (that lack TCR) suggest that the gating of these channels was altered. Knockdown of Cav1.1 channels in T cells abrogated calcium entry after TCR stimulation, suggesting that Cav1.1 channels are controlled by TCR signaling.
doi:10.1371/journal.pone.0147379
PMCID: PMC4729531  PMID: 26815481
18.  Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells 
Nature immunology  2015;16(8):871-879.
Memory CD8+ T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4+ regulatory T cells (Treg cells) was necessary for the maturation of memory CD8+ T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell–derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase ‘restored’ the maturation of memory CD8+ T cells in IL-10-deficient mice. Our data indicate that Treg cell–derived IL-10 is needed to insulate CD8+ T cells from inflammatory signals, and reveal that the resolution phase of infection is a critical period that influences the quality and function of developing memory CD8+ T cells.
doi:10.1038/ni.3224
PMCID: PMC4713030  PMID: 26147684
19.  Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA 
Cell  2014;159(7):1563-1577.
The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify of a mechanism by which mitochondria and downstream pro-apoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response, and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a pro-inflammatory type of cell death.
doi:10.1016/j.cell.2014.11.037
PMCID: PMC4272443  PMID: 25525875
20.  Producing GM-CSF: a unique T helper subset? 
Cell Research  2014;24(12):1379-1380.
GM-CSF-producing helper T cells have previously been identified to serve a nonredundant function in the initiation of autoimmune inflammation. An article by Sheng et al. recently published by Cell Research now suggests that the differentiation program of GM-CSF-producing cells from naïve CD4+ T cells is distinct from that of Th1 and Th17 cells, and is regulated by the IL-7-STAT5 axis.
doi:10.1038/cr.2014.155
PMCID: PMC4260353  PMID: 25412663
22.  Detecting “different”: Pyrin senses modified GTPases 
Cell Research  2014;24(11):1286-1287.
Pathogenic bacteria secrete effector proteins that target host cell Rho GTPases to manipulate the actin cytoskeleton. A recent study in Nature identifies the Pyrin inflammasome as a sensor of this pathogenic process.
doi:10.1038/cr.2014.101
PMCID: PMC4220150  PMID: 25091449
23.  Inflammasome Activation by Campylobacter jejuni 
The Gram-negative pathogen Campylobacter jejuni is the most common cause of bacterial foodborne disease worldwide. The mechanisms that lead to bacterial invasion of eukaryotic cells and massive intestinal inflammation are still unknown. Here we report that C. jejuni infection of mouse macrophages induces up-regulation of pro-IL-1β transcript and secretion of IL-1β without eliciting cell death. Immunoblotting indicated cleavage of caspase-1 and IL-1β in infected cells. In bone-marrow-derived macrophages from different knock-out mice, IL-1β secretion was found to require NLRP3, ASC, and caspase-1/11, but not NLRC4. In contrast to NLRP3 activation by ATP, C. jejuni activation did not require priming of these macrophages. C. jejuni also activated the NLRP3 inflammasome in human macrophages as indicated by the presence of ASC foci and FLICA-positive cells. Analysis of a vast array of C. jejunimutants with defects in capsule formation, LOS biosynthesis, chemotaxis, flagella synthesis and flagellin (-like) secretion, T6SS needle protein or cytolethal distending toxin revealed a direct correlation between the number of intracellular bacteria and NLRP3 inflammasome activation. The C. jejuni invasion related activation of the NLRP3 inflammasome without cytotoxicity and even in non-primed cells extends the known repertoire of bacterial inflammasome activation and likely contributes to C. jejuni-induced intestinal inflammation.
doi:10.4049/jimmunol.1400648
PMCID: PMC4201959  PMID: 25267974
NLRP3; C. jejuni; Inflammation; Macrophages; Human; Mice; Invasion; Inflammasome
24.  Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota 
International Immunology  2014;26(9):495-499.
Inflammasomes control intestinal homeostasis
Inflammasomes are large cytosolic protein complexes that detect infection and stress-associated signals and promote immediate inflammatory responses. In the intestine, activation of the inflammasome leads to an inflammatory response that is important for controlling enteric infections but can also result in pathological tissue damage. Recent studies have suggested that the inflammasome also regulates intestinal homeostasis through its effects on the intestinal microbiota. Notably, many conflicting studies have been published regarding the effect of inflammasome deficiencies on intestinal homeostasis. Here, we attempt to reconcile these contrasting data by highlighting the many ways that the inflammasome contributes to intestinal homeostasis and pathology and exploring the potential role of alterations in the microbiota in these conflicting studies.
doi:10.1093/intimm/dxu066
PMCID: PMC4200027  PMID: 24948595
IBD; infection; inflammasome; intestine; microbiota
25.  Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease 
Cell  2014;158(5):1000-1010.
SUMMARY
Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA−SEQ) and show that high IgA−coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA−SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with pre-defined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA−coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.
doi:10.1016/j.cell.2014.08.006
PMCID: PMC4174347  PMID: 25171403

Results 1-25 (289)