37 results found
Olona A, Hateley C, Guerrero A, et al., 2022, Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis, British Journal of Pharmacology, Vol: 179, Pages: 1874-1886, ISSN: 0007-1188
Background and purpose: Cardiac glycosides (CGs) inhibit the Na+,K+‐ATPase and are widely prescribed medicines for chronic heart failure and cardiac arrhythmias. Recently, CGs have been described to induce inflammasome activation and pyroptosis in human macrophages, suggesting a cytotoxicity that remains to be elucidated in tissues.Experimental approach: To determine the cell type specificity of CG‐mediated cytotoxicity, we used human primary monocyte‐derived macrophages (hMDMs) and non‐adherent peripheral blood cells isolated from healthy donors. Omental white adipose tissue (WAT) and stromal vascular fraction (SVF)‐derived pre‐adipocytes and adipocytes were isolated from obese patients undergoing bariatric surgery. All these primary cells/tissues were treated with nanomolar concentrations of ouabain (50nM, 100nM and 500nM) to investigate its degree of cytotoxicity and mechanisms leading to cell death. In WAT, we further explored the consequences of ouabain‐mediated cytotoxicity by measuring insulin sensitivity, adipose tissue function and extracellular matrix (ECM) deposition ex vivo.Key results: The ouabain‐induced cell death is through pyroptosis and apoptosis, and more efficient in hMDMs compared to non‐adherent PBMC populations. This selective cytotoxicity is dependent on K+ flux, as ouabain causes an intracellular depletion of K+, while inducing accumulation of Na+ and Ca2+ levels. Consistently, the cell‐death caused by these ion imbalances can be rescued by addition of potassium chloride in hMDMs. Remarkably, when WAT explants from obese patients are cultured with nanomolar concentrations of ouabain, this causes depletion of macrophages, down‐regulation of type VI collagen levels, and amelioration of insulin sensitivity ex vivo.Conclusions and implications: These results suggest that the usage of nanomolar concentration of CGs can be an attractive therapeutic avenue in metabolic syndrome characterised by pathogenic infiltration and activation of macrophages.
Hamilton C, Olona A, Leishman S, et al., 2021, NLRP3 inflammasome priming and activation are regulated by a novel phosphatidylinositol-dependent mechanism, Publisher: bioRxiv
Imbalance in lipid homeostasis is associated with discrepancies in immune signalling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signalling, however, remain ambiguous. The phospholipid phosphatidylinositol (PI), which is implicated in numerous immune disorders, is chiefly defined by its phosphorylation status. By contrast, the significance of the two fatty acid chains attached to the PI remains unknown. Here, by employing a mass-spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NLRP3 inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ABCB1, which effluxes lipid derivatives, revealed defective inflammasome activation. Mechanistically, Abcb1-deficiency shifted the total PI configuration exhibiting a reduced ratio of short-chain to long-chain PI-acyl lipids. Consequently, Abcb1-deficiency resulted in rapid degradation of TIRAP, the TLR adaptor protein which binds PI(4,5)-phosphate. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser293 position and blunted inflammasome activation. Exogenously supplementing WT cells with linoleic acid, but not arachidonic acid, reconfigured PI acyl chains. Accordingly, linoleic acid supplementation increased TIRAP degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Altogether, our study reveals a novel metabolic-inflammatory circuit which contributes to calibrating immune responses.
Anand P, 2020, Lipids, inflammasomes, metabolism and disease, Immunological Reviews, Vol: 297, Pages: 108-122, ISSN: 0105-2896
Inflammasomes are multi‐protein complexes that regulate the cleavage of cysteine protease caspase‐1, secretion of inflammatory cytokines, and induction of inflammatory cell death, pyroptosis. Several members of the nod‐like receptor family assemble inflammasome in response to specific ligands. An exception to this is the NLRP3 inflammasome which is activated by structurally diverse entities. Recent studies have suggested that NLRP3 might be a sensor of cellular homeostasis, and any perturbation in distinct metabolic pathways results in the activation of this inflammasome. Lipid metabolism is exceedingly important in maintaining cellular homeostasis, and it is recognized that cells and tissues undergo extensive lipid remodeling during activation and disease. Some lipids are involved in instigating chronic inflammatory diseases, and new studies have highlighted critical upstream roles for lipids, particularly cholesterol, in regulating inflammasome activation implying key functions for inflammasomes in diseases with defective lipid metabolism. The focus of this review is to highlight how lipids regulate inflammasome activation and how this leads to the progression of inflammatory diseases. The key roles of cholesterol metabolism in the activation of inflammasomes have been comprehensively discussed. Besides, the roles of oxysterols, fatty acids, phospholipids, and lipid second messengers are also summarized in the context of inflammasomes. The overriding theme is that lipid metabolism has numerous but complex functions in inflammasome activation. A detailed understanding of this area will help us develop therapeutic interventions for diseases where dysregulated lipid metabolism is the underlying cause.
Lupfer CR, Anand PK, Qi X, et al., 2020, Editorial: role of NOD-like receptors in infectious and immunological diseases, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224
Lukens JR, Anand PK, 2020, Adapt(ed) to repair — TH2 immune responses in the bladder promote recurrent infections, Nature Immunology, Vol: 21, Pages: 597-599, ISSN: 1529-2908
Hamilton C, Larrouy-Maumus G, Anand P, 2020, Phosphatidylinositol Acyl Chains Configure TLR-Dependent Priming and Activation of the NLRP3 Inflammasome, BioRxiv 2020
Abstract Lipids are important in establishing cellular homeostasis by conducting varied functions including relay of extracellular signals. Imbalance in lipid homeostasis results in metabolic diseases, and is tightly connected to discrepancies in immune signalling. The phosphorylation status of the lipid second messenger phosphatidylinositol phosphates is implicated in key physiological functions and pathologies. By contrast, little is known as to how phosphatidylinositol (PI) lipid acyl chains contribute to cellular processes. Here, by employing a mass-spectrometry-based method, we show a role for PI acyl group chains in regulating NLRP3 inflammasome activation in cells lacking ABC transporter ABCB1. In response to canonical stimuli, Abcb1 -/- cells revealed defective priming and activation of the NLRP3 inflammasome owing to blunted TLR-dependent signalling. Cellular lipidomics demonstrated that ABC transporter deficiency shifted the total PI balance such that Abcb1 -/- cells exhibited reduced ratio of the short-chain to long-chain acyl chain lipids. Changes in PI acyl chain configuration accompanied diminished levels of ganglioside GM1, a marker of cholesterol-rich membrane microdomains, in deficient cells. Strikingly, this was not due to differences in the expression of enzymes that either synthesize PI or are involved in acyl chain remodelling. Our study thus suggests an important role for PI lipid chains in priming and activation of the NLRP3 inflammasome thereby highlighting the metabolic regulation of immune responses.
Hamilton C, Anand PK, 2019, Right place, right time: Localisation and assembly of the NLRP3 inflammasome, F1000Research, Vol: 8, ISSN: 2046-1402
The NLRP3 inflammasome is a multimeric protein complex that cleavescaspase-1 and the pro-inflammatory cytokines interleukin 1 beta (IL-1β)and IL-18. Dysregulated NLRP3 inflammasome signalling is linked toseveral chronic inflammatory and autoimmune conditions; thus,understanding the activation mechanisms of the NLRP3 inflammasome isessential. Studies over the past few years have implicated vital roles fordistinct intracellular organelles in both the localisation and assembly of the NLRP3 inflammasome. However, conflicting reports exist. Prior to itsactivation, NLRP3 has been shown to be resident in the endoplasmicreticulum (ER) and cytosol, although, upon activation, the NLRP3inflammasome has been shown to assemble in the cytosol, mitochondria,and mitochondria-associated ER membranes by different reports. Finally,very recent work has suggested that NLRP3 may be localised on oradjacent to the Golgi apparatus and that release of mediators from thisorganelle may contribute to inflammasome assembly. Therefore, NLRP3may be strategically placed on or in close proximity to these subcellularcompartments to both sense danger signals originating from theseorganelles and use the compartment as a scaffold to assemble thecomplex. Understanding where and when NLRP3 inflammasome assembly occurs may help identify potential targets for treatment of NLRP3-related disorders.
Lupfer CR, Rippee-Brooks M, Anand P, 2019, Common differences: the ability of inflammasomes to distinguish between self and pathogen nucleic acids during infection, International Review of Cell and Molecular Biology, Vol: 344, Pages: 139-172, ISSN: 1937-6448
The innate immune system detects the presence of pathogens based on detection of non-self. In other words, most pathogens possess intrinsic differences that can distinguish them from host cells. For example, bacteria and fungi have cell walls comprised of peptidoglycan and carbohydrates (like mannans), respectively. Germline encoded pattern recognition receptors (PRRs) of the Toll-like receptor (TLR) and C-type lectin receptor (CLR) family have the ability to detect such unique pathogen associated features. However, some TLRs and members of the RIG-I-like receptor (RLR), NOD-like receptor (NLR), or AIM2-like receptor (ALR) family can sense pathogen invasion based on pathogen nucleic acids. Nucleic acids are not unique to pathogens, thus raising the question of how such PRRs evolved to detect pathogens but not self. In this chapter, we will examine the PRRs that sense pathogen nucleic acids and subsequently activate the inflammasome signaling pathway. We will examine the selective mechanisms by which these receptors distinguish pathogens from “self” and discuss the importance of such pathways in disease development in animal models and human patients.
De la Roche M, Hamilton C, Mortensen R, et al., 2018, Trafficking of cholesterol to the ER is required for NLRP3 inflammasome activation, Journal of Cell Biology, Vol: 217, ISSN: 0021-9525
Cellular lipids determine membrane integrity and fluidity and are being increasingly recognized to influence immune responses. Cellular cholesterol requirements are fulfilled through biosynthesis and uptake programs. In an intricate pathway involving the lysosomal cholesterol transporter NPC1, the sterol gets unequally distributed across intracellular compartments. By using pharmacological and genetic approaches targeting NPC1, we reveal that blockade of cholesterol trafficking through the late endosome–lysosome pathway blunts NLRP3 inflammasome activation. Altered cholesterol localization at the plasma membrane (PM) in Npc1−/− cells abrogated AKT–mTOR signaling by TLR4. However, the inability to activate the NLRP3 inflammasome was traced to perturbed cholesterol trafficking to the ER but not the PM. Accordingly, acute cholesterol depletion in the ER membranes by statins abrogated casp-1 activation and IL-1β secretion and ablated NLRP3 inflammasome assembly. By contrast, assembly and activation of the AIM2 inflammasome progressed unrestricted. Together, this study reveals ER sterol levels as a metabolic rheostat for the activation of the NLRP3 inflammasome.
Hamilton C, Tan L, Miethke T, et al., 2017, Immunity to uropathogens: the emerging roles of inflammasomes, Nature Reviews Urology, Vol: 14, Pages: 284-295, ISSN: 1759-4812
Urinary tract infections (UTIs) cause a huge burden of morbidity worldwide with recurrence of UTIs becoming significantly frequent due to the emergence of antibiotic-resistant bacterial strains. Recent research has focussed on interactions between the innate and adaptive immune responses to pathogens colonizing the urinary tract. Inflammasomes are part of the innate immune defense and respond rapidly to several infectious diseases. Assembly of the multiprotein inflammasome complex activates Caspase-1, processes proinflammatory cytokines IL-1β and IL-18, and induces pyroptosis. These effector pathways, in turn, act at different levels to either prevent or resolve infection, or eliminate the infectious agent itself. Whilst in certain instances inflammasome activation promotes tissue pathology, the precise functions of inflammasomes in UTIs remain unexplored. In this review, we discuss recent studies on the roles of inflammasomes in UTIs with a particular focus on common infections of the urinary tract. An improved understanding of inflammasomes may provide valuable novel approaches for the design of diagnostics and therapeutics for complicated UTIs, thus enabling us to counteract the challenge of drug resistance.
Lupfer C, Anand PK, 2016, Integrating inflammasome signaling in sexually transmitted infections, Trends in Immunology, Vol: 37, Pages: 703-714, ISSN: 1471-4981
Inflammasomes are cytosolic multiprotein platforms with pivotal roles in infectious diseases. Activation of inflammasomes results in pro-inflammatory cytokine signaling and pyroptosis. Sexually transmitted infections are a major health problem worldwide, yet few studies have probed the impact of inflammasome signaling during these infections. Due to the dearth of appropriate infection models, our current understanding of inflammasomes in sexually transmitted infections is mostly drawn from results obtained in vitro, from distant infection sites, or from related microbial strains that are not sexually transmitted. Understanding how inflammasomes influence the outcome of sexually transmitted infections may lead to the development of novel and effective strategies to control disease and prevent transmission.Here, we discuss and highlight the recent progress in this field.
Lupfer CR, Anand PK, Liu Z, et al., 2014, Reactive Oxygen Species Regulate Caspase-11 Expression and Activation of the Non-canonical NLRP3 Inflammasome during Enteric Pathogen Infection, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
Gurung P, Anand PK, Malireddi RKS, et al., 2014, FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes, Journal of Immunology, Vol: 192, Pages: 1835-1846, ISSN: 0022-1767
The Nlrp3 inflammasome is critical for host immunity, but the mechanisms controlling its activation are enigmatic. In this study, we show that loss of FADD or caspase-8 in a RIP3-deficient background, but not RIP3 deficiency alone, hampered transcriptional priming and posttranslational activation of the canonical and noncanonical Nlrp3 inflammasome. Deletion of caspase-8 in the presence or absence of RIP3 inhibited caspase-1 and caspase-11 activation by Nlrp3 stimuli but not the Nlrc4 inflammasome. In addition, FADD deletion prevented caspase-8 maturation, positioning FADD upstream of caspase-8. Consequently, FADD- and caspase-8–deficient mice had impaired IL-1β production when challenged with LPS or infected with the enteropathogen Citrobacter rodentium. Thus, our results reveal FADD and caspase-8 as apical mediators of canonical and noncanonical Nlrp3 inflammasome priming and activation.
Anand PK, Kanneganti T-D, 2013, NLRP6 in infection and inflammation, MICROBES AND INFECTION, Vol: 15, Pages: 661-668, ISSN: 1286-4579
Lupfer C, Thomas PG, Anand PK, et al., 2013, Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection, NATURE IMMUNOLOGY, Vol: 14, Pages: 480-+, ISSN: 1529-2908
Buffen K, Oosting M, Mennens S, et al., 2013, Autophagy Modulates Borrelia burgdorferi-induced Production of Interleukin-1 beta (IL-1 beta), JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 8658-8666
Anand PK, Kanneganti T-D, 2012, Targeting NLRP6 to enhance immunity against bacterial infections, FUTURE MICROBIOLOGY, Vol: 7, Pages: 1239-1242, ISSN: 1746-0913
Gurung P, Malireddi RKS, Anand PK, et al., 2012, Toll or Interleukin-1 Receptor (TIR) Domain-containing Adaptor Inducing Interferon-beta (TRIF)-mediated Caspase-11 Protease Production Integrates Toll-like Receptor 4 (TLR4) Protein- and Nlrp3 Inflammasome-mediated Host Defense against Enteropathogens, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 34474-34483
Anand PK, Malireddi RKS, Lukens JR, et al., 2012, NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens, NATURE, Vol: 488, Pages: 389-+, ISSN: 0028-0836
Anand PK, Tait SWG, Lamkanfi M, et al., 2011, TLR2 and RIP2 Pathways Mediate Autophagy of Listeria monocytogenes via Extracellular Signal-regulated Kinase (ERK) Activation, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 42981-42991
Zaki MH, Vogel P, Malireddi RKS, et al., 2011, The NOD-Like Receptor NLRP12 Attenuates Colon Inflammation and Tumorigenesis, CANCER CELL, Vol: 20, Pages: 649-660, ISSN: 1535-6108
Anand PK, Malireddi RKS, Kanneganti T-D, 2011, Role of the Nlrp3 inflammasome in microbial infection, FRONTIERS IN MICROBIOLOGY, Vol: 2, ISSN: 1664-302X
Hoffmann E, Marion S, Mishra BB, et al., 2010, Initial receptor-ligand interactions modulate gene expression and phagosomal properties during both early and late stages of phagocytosis, EUROPEAN JOURNAL OF CELL BIOLOGY, Vol: 89, Pages: 693-704, ISSN: 0171-9335
Anand PK, 2010, Exosomal membrane molecules are potent immune response modulators., Commun Integr Biol, Vol: 3, Pages: 405-408
Exosomes are endosome-derived vesicles (40-100 nm) formed during the formation of multi-vesicular bodies (MVBs). Occasionally, the MVBs fuse with the plasma membrane releasing their intra-luminal vesicles into the extracellular media, which are then known as exosomes. Different cell types such as B-cells, dendritic cells, platelets, reticulocytes and macrophages can release exosomes and current research in this area is more focused towards exosomes released by antigen-presenting cells. Exosomes have recently been shown to be immunomodulatory and the mechanism of immune response initiation by them is beginning to emerge. Besides molecules present inside the lumen of exosomes, it has been suggested that certain exosomal membrane molecules can interact with their surface receptors on the target cells thereby inducing an immunomodulatory response. In this review, Hsp70 and galectin-5, two immunogenic molecules present on exosomal membrane, are discussed in detail for initiating this response.
Anand PK, Anand E, Bleck CKE, et al., 2010, Exosomal Hsp70 Induces a Pro-Inflammatory Response to Foreign Particles Including Mycobacteria, PLOS ONE, Vol: 5, ISSN: 1932-6203
Kuehnel MP, Rybin V, Anand PK, et al., 2009, Lipids regulate P2X7-receptor-dependent actin assembly by phagosomes via ADP translocation and ATP synthesis in the phagosome lumen, JOURNAL OF CELL SCIENCE, Vol: 122, Pages: 499-504, ISSN: 0021-9533
Kuehnel MP, Reiss M, Anand PK, et al., 2009, Sphingosine-1-phosphate receptors stimulate macrophage plasma-membrane actin assembly via ADP release, ATP synthesis and P2X7R activation, JOURNAL OF CELL SCIENCE, Vol: 122, Pages: 505-512, ISSN: 0021-9533
Anand PK, Kaul D, Sharma M, 2008, Synergistic action of vitamin D and retinoic acid restricts invasion of macrophages by pathogenic mycobacteria, JOURNAL OF MICROBIOLOGY IMMUNOLOGY AND INFECTION, Vol: 41, Pages: 17-25, ISSN: 1684-1182
Chaudhry A, Anand PK, Singh GS, et al., 2006, Ectopic pairing of the intercalary heterochromatin in the organophosphate pesticide treated mosquito chromosomes (Culcidae: Diptera), Cytologia, Vol: 71, Pages: 431-437, ISSN: 0011-4545
The extensive use of chemical pesticides has greatly increased the mutational load on the genome of living organisms. The problems of genetic toxicology have generated more concern than any other problem because the residual inclusion of pesticides in the environment leads to a number of direct and indirect effects on the genetic material. Induced chromosomal mutations provide a reliable index of the mutagenic potential of a chemical or a physical agent. Experience has shown that the mutagenic effect of the semilethal doses of chemicals induce a of variety of structural changes in the polytene chromosomes out of which ectopic pairings are the most frequent types of aberrations. As a consequence of these points of genetic interest, the present paper deals with the incidence of ectopic pairing of the intercalary heterochromatic bands in the polytene chromosomes of those larvae of Anopheles subpictus, which were treated with LC20 of 4 organophosphate pesticides viz. chlorpyrifos, monocrotophos, acephate and dimethoate. When compared with the data of non-treated controls the treated larvae had an elevated incidence of intercalary heterchromatic linkages in the X-chromosome and the right and left arms of autosomes 2 and 3 (2R, 2L, 3R, 3L). The results are discussed in relevance to the fact that ectopic associations are established between those heterochromatic bands which are homologous in their chemical and genetic properties. These properties are attributed to the presence of identical A : T rich nucleotide sequences resulting from gene duplications which are induced by the cellular environments altered by the pesticides. © 2006 The Japan Mendel Society.
Kaul D, Anand PK, Khanna A, 2006, Functional genomics of PPAR-gamma in human immunomodulatory cells, MOLECULAR AND CELLULAR BIOCHEMISTRY, Vol: 290, Pages: 211-215, ISSN: 0300-8177
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