Jatinder K Juss

University of Cambridge, Cambridge, England, United Kingdom

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Publications (14)148.71 Total impact

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    ABSTRACT: We identified a novel, evolutionarily conserved receptor encoded within the human leukocyte receptor complex and syntenic region of mouse chromosome 7, named T cell-interacting, activating receptor on myeloid cells-1 (TARM1). The transmembrane region of TARM1 contained a conserved arginine residue, consistent with association with a signaling adaptor. TARM1 associated with the ITAM adaptor FcRγ but not with DAP10 or DAP12. In healthy mice, TARM1 is constitutively expressed on the cell surface of mature and immature CD11b(+)Gr-1(+) neutrophils within the bone marrow. Following i.p. LPS treatment or systemic bacterial challenge, TARM1 expression was upregulated by neutrophils and inflammatory monocytes and TARM1(+) cells were rapidly recruited to sites of inflammation. TARM1 expression was also upregulated by bone marrow-derived macrophages and dendritic cells following stimulation with TLR agonists in vitro. Ligation of TARM1 receptor in the presence of TLR ligands, such as LPS, enhanced the secretion of proinflammatory cytokines by macrophages and primary mouse neutrophils, whereas TARM1 stimulation alone had no effect. Finally, an immobilized TARM1-Fc fusion protein suppressed CD4(+) T cell activation and proliferation in vitro. These results suggest that a putative T cell ligand can interact with TARM1 receptor, resulting in bidirectional signaling and raising the T cell activation threshold while costimulating the release of proinflammatory cytokines by macrophages and neutrophils.
    No preview · Article · Aug 2015 · The Journal of Immunology
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    ABSTRACT: This is the author accepted manuscript. It is currently under an indefinite embargo pending publication of the final version.
    Full-text · Article · Jul 2015
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    ABSTRACT: Human cytomegalovirus (HCMV) causes significant morbidity in the immunocompromised host. Following primary infection, the virus establishes latency in progenitor cells of the myeloid lineage. These cells exhibit limited viral gene transcription and no evidence of de novo virion production. It is well recognised that differentiation of latently infected myeloid progenitor cells to dendritic or macrophage-like cells permits viral reactivation in vitro. This has been used to support the concept that viral reactivation in HCMV carriers routinely occurs from such terminally differentiated myeloid cells in vivo. However, to date this has not been shown for in vivo-differentiated macrophages. We demonstrate for the first time that alveolar macrophages from HCMV carriers express immediate early lytic genes and produce infectious virus. This supports the view, up until now based on in vitro data, that terminally differentiated myeloid cells in vivo are sites of HCMV reactivation and potential centres of viral dissemination in latently infected individuals with no evidence of virus disease or dissemination. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Full-text · Article · Dec 2014 · The Journal of Infectious Diseases
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    ABSTRACT: Human rhinoviruses (HRV) are a major cause of exacerbations of airways disease. Aspects of cell signalling responses to HRV infection remain unclear, particularly with regard to signalling via PI3K, and the PI3K-dependent pathway, autophagy. We investigated the roles of PI3K and autophagy in the responses of epithelial cells to major and minor group HRV infection. The PI3K inhibitor 3-MA, commonly used to inhibit autophagy, markedly reduced HRV-induced cytokine induction. Further investigation of potential targets of 3-MA and comparison of results using this inhibitor to a panel of general and class I-selective PI3K inhibitors showed that several PI3Ks cooperatively regulate responses to HRV. Targeting by siRNA of the autophagy proteins Beclin-1, Atg7, LC3, alone or in combination, or targeting of the autophagy-specific class III PI3K had at most only modest effects on HRV-induced cell signalling as judged by induction of proinflammatory cytokine production. Our data indicate that PI3K and mTOR are involved in induction of proinflammatory cytokines after HRV infection, and that autophagy has little role in the cytokine response to HRV or control of HRV replication.
    Preview · Article · Dec 2014 · PLoS ONE
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    ABSTRACT: Neutrophil recruitment into the bronchoalveolar space is central to the pathogenesis of acute respiratory distress syndrome injury (ARDS), and occurs via interaction with the lung microvascular endothelium. Tumour Necrosis Factor (TNF) is a key mediator in these processes, activating endothelial cells and inducing changes in microvascular permeability, as well as priming neutrophils (a pre-requisite for neutrophil-mediated tissue damage) and modulating neutrophil lifespan. TNF signals through two cell surface receptors, TNFR1 and TNFR2 initiating distinct signalling pathways and cellular responses. In a human in vivo model of ARDS, selective TNFR1 antagonism attenuated pulmonary inflammation (O’Kane et al, Thorax 2013; 63:A50). Using TNF receptor specific muteins and a novel highly selective TNFR1 antagonist, we investigated the role of differential TNFR signalling on neutrophil-pulmonary microvascular endothelial cell interactions. TNF-induced alterations in the expression of the neutrophil cell surface molecules CD11b, CD62L, TNFR1 and TNFR2 were all modulated via TNFR1. TNFR1 was also the dominant receptor mediating reactive oxygen species generation by TNF-primed, fMLP-stimulated neutrophils. We further examined the role of TNF receptors in modulating neutrophil apoptosis; whilst engagement of both TNFR1 and 2 was required to induce early neutrophil apoptosis, TNFR1 antagonism reversed TNF-induced late survival to constitutive levels of apoptosis. TNFR1 antagonsim of human pulmonary microvascular endothelial monolayers significantly reduced TNF-induced production of IL-1beta, IL-6 and IL-8 (p < 0.05), endothelial permeability and the release of the endothelial injury markers sICAM-1, sVCAM-1 and sE-selectin (p Collectively, these results suggest that TNFR1 regulates multiple components of neutrophil-endothelial interactions. Selective TNFR1 antagonism may offer a novel therapeutic approach in ARDS; phase II clinical trials of this therapy are scheduled.
    No preview · Article · Dec 2014 · Thorax
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    ABSTRACT: Introduction and objectives Neutrophils (PMNs) are a key component of the innate immune response to invading pathogens. They accumulate at sites of inflammation and infection, which are typically characterised by low oxygen tensions (e.g. in the acute respiratory distress syndrome (ARDS)). Human PMNs undergo constitutive apoptosis, their survival contingent upon pro-survival and pro-apoptotic signals derived from their microenvironment. Hypoxia profoundly delays PMN apoptosis, resulting in persistence of PMNs at inflammatory foci and this may perpetuate hypoxia-mediated lung injury. Given the importance of phosphoinositide 3-kinase (PI3-K) signalling in cytokine-mediated neutrophil survival, we hypothesised that hypoxia-induced PMN survival may also involve PI3-K-mediated signalling. Methods Highly pure PMNs isolated from healthy volunteers were incubated for 20 h under normoxic (20 kPa) and physiologically relevant hypoxic (3 kPa) conditions with a pan-PI3-K inhibitor (LY294002 at 10 μM), a novel pan-Class I PI3-K inhibitor (ZSTK474 at 1 μM, 3 μM and 10 μM) or novel PI3-K Class I isoform-selective inhibitors (PI3-Kδ at 1 μM; PI3-Kγ at 3 μM and 10 μM, or PI3-Kδγ at 3 μM). PMNs were also incubated in normoxia and hypoxia in the presence of GM-CSF (1 ng/ml) with the same panel of inhibitors, allowing comparison with GM-CSF mediated survival, which is largely PI3-K dependent. PMN apoptosis was assessed using two complementary techniques – morphology and flow cytometry following annexin V-FITC and propidium iodide staining. Results Compared with normoxia, hypoxia promoted PMN survival (mean% ± SEM apoptotic cells at 20 h; 30.9 ± 1.9 vs. 59.0 ± 1.8 respectively, p < 0.0001). Both pan-PI3-K inhibitors reversed the pro-survival effect of hypoxia in a concentration-dependent manner, LY294002 (10 μM; 60.3 ± 4.0, p < 0.0001) and ZSTK474 (10 μM; 58.3 ± 2.6, p < 0.0001) without affecting the basal rate of apoptosis. This effect was not seen with the dual PI3-Kδγ inhibitor (3 μM; 43.8 ± 7.6) or individual PI3-Kδ (1 μM; 43.0 ± 5.8) and γ inhibitors (3 μM; 34.9 ± 4.5 and 10 μM; 32.6 ± 3.6). Conclusions Our results indicate that hypoxia-induced PMN survival is PI3-K dependent. Targeting this pathway may accelerate PMN apoptosis, resulting in resolution of inflammation.
    No preview · Article · Dec 2014 · Thorax
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    ABSTRACT: Inappropriate accumulation or persistence of neutrophils (polymorphonuclear leucocytes [PMNs]), within the alveolar airspace is considered to be crucial to the pathogenesis of acute respiratory distress syndrome (ARDS). Previous work has established that alveolar PMNs from patients with ARDS have a pro-survival phenotype, and that bronchoalveolar lavage fluid (BALF) in ARDS suppresses constitutive PMN apoptosis in vitro. However, the functional activity of alveolar-sequestered PMNs in ARDS is unknown, partly due to the technical challenges in obtaining and purifying alveolar PMNs. Proinflammatory mediators in the ARDS alveolar milieu conceivably prime or activate key PMN functions in vivo, including the generation of toxic reactive oxygen species (ROS). This research evaluates agonist-stimulated ROS generation in alveolar and blood PMNs from the same patient with ARDS compared with healthy volunteer blood PMNs.
    No preview · Article · Feb 2014 · The Lancet
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    ABSTRACT: Genetic mutations cause primary immunodeficiencies (PIDs), which predispose to infections. Here we describe Activated PI3K-δ Syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.
    No preview · Article · Oct 2013 · Science
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    ABSTRACT: We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δ(KO)γ(KO) or p110γ(KO)). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110δ(KO)γ(KO) mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway.
    Full-text · Article · Sep 2012 · PLoS ONE
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    ABSTRACT: Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying the resolution of eosinophilic inflammation and studies have indicated the ability of interventions that induce human eosinophil apoptosis to promote the resolution of eosinophilic inflammation. Recently, the cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to enhance neutrophil apoptosis and promote the resolution of neutrophilic inflammation. The purpose of this study was to examine the expression of CDKs in human blood eosinophils, the effects of R-roscovitine on eosinophil survival in vitro and whether R-roscovitine could influence eosinophilic lung inflammation in vivo. Eosinophils were isolated from human peripheral blood and the effects of R-roscovitine on apoptosis, degranulation and phagocytic uptake examined in vitro. The effects of R-roscovitine on eosinophilic lung inflammation in vivo were also assessed using an ovalbumin mouse model. Our data demonstrate that human eosinophils express five known targets for R-roscovitine: CDK1, -2, -5, -7 and -9. R-roscovitine induced eosinophil apoptosis in a time- and concentration-dependent manner but also accelerated transition to secondary necrosis as assessed by microscopy, flow cytometry and caspase activation. In addition, we show that R-roscovitine can override the anti-apoptotic signals of GM-CSF and IL-5. We report that the pro-apoptotic effect of R-roscovitine is associated with suppression of Mcl-1L expression and that this compound enhanced phagocytic clearance of eosinophils by macrophages. Finally, we show that R-roscovitine induces apoptosis in murine peripheral blood and spleen-derived eosinophils; despite this, R-roscovitine did not modulate the tissue and lumen eosinophilia characteristic of the ovalbumin mouse model of airway eosinophilia. These data demonstrate that R-roscovitine is capable of inducing rapid apoptosis and secondary necrosis in eosinophils but does not affect the onset or improve the resolution of eosinophilic airway inflammation in vivo.
    Full-text · Article · May 2011 · Clinical & Experimental Allergy
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    ABSTRACT: Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (FcγRs). Here, we used genetic and pharmacological approaches to define a selective role for the β isoform of phosphoinositide 3-kinase (PI3Kβ) in FcγR-dependent activation of mouse neutrophils by immune complexes of IgG and antigen immobilized on a plate surface. At low concentrations of immune complexes, loss of PI3Kβ alone substantially inhibited the production of reactive oxygen species (ROS) by neutrophils, whereas at higher doses, similar suppression of ROS production was achieved only by targeting both PI3Kβ and PI3Kδ, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3Kβ by immune complexes involved cooperation between FcγRs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B₄. Coincident activation by a tyrosine kinase-coupled receptor (FcγR) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the β isoform of PI3K. PI3Kβ-deficient mice were highly protected in an FcγR-dependent model of autoantibody-induced skin blistering and were partially protected in an FcγR-dependent model of inflammatory arthritis, whereas combined deficiency of PI3Kβ and PI3Kδ resulted in near-complete protection in the latter case. These results define PI3Kβ as a potential therapeutic target in inflammatory disease.
    Full-text · Article · Apr 2011 · Science Signaling

  • No preview · Article · Dec 2010 · Thorax
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    ABSTRACT: Introduction Neutrophils are an essential component of the innate immune response. However, their microbicidal mechanisms (generation of reactive oxygen species and release of proteolytic enzymes) may contribute to tissue injury. Neutrophil-mediated tissue damage is a cardinal feature in the pathogenesis/progression of COPD, cystic fibrosis and certain types of asthma. Apoptosis is the key determinant of tissue neutrophil longevity and is critical to the resolution of granulocyte inflammation; pharmacological acceleration of neutrophil apoptosis can promote resolution of inflammation in animal models. The cytokine GM-CSF drives the aberrant neutrophil survival phenotype observed in patients with ARDS, and recent studies suggest the phosphoinositide 3-kinase (PI3K)/AKT pathway is pivotal in signalling GM-CSF-mediated neutrophil survival. Hypothesis Given the emerging evidence that individual Class I PI3K isoforms (α, β, δ and γ) exert non-redundant signalling roles and represent promising therapeutic targets in inflammation, we hypothesised a distinct contribution of individual Class I PI3K isoforms in mediating constitutive neutrophil apoptosis and the GM-CSF cytoprotective effect. Methods We established techniques to isolate peripheral blood neutrophils from humans and from knockout/transgenic mice lacking functional PI3K isoforms to 95% purity, and used pan-PI3K inhibitor (LY294002), pan-Class I PI3K inhibitor (PI-103) and novel PI3K isoform-selective small molecule inhibitors (YM-024, TGX-221, IC87114 and AS605240) to determine precise involvement of Class I PI3K isoforms (α, β, δ and γ) in constitutive and GM-CSF-delayed neutrophil apoptosis. Apoptosis was quantified using morphology and annexin V-FITC/propidium iodide staining. Results GM-CSF-mediated neutrophil survival was reversed by pan-PI3K inhibition but not by individual PI3K isoform inhibition. Combinatorial experiments suggest there is near-complete functional redundancy amongst Class I PI3Ks with regard to GM-CSF-mediated inhibition of neutrophil apoptosis; additionally, neutrophils derived from double knockout PI3K-δ/γ and PI3K-β/δ mice had normal constitutive apoptosis and GM-CSF mediated survival, but were sensitised to inhibition of the remaining isoforms. Conclusions Thus Class I PI3Ks mediate GM-CSF survival of human and murine neutrophils but there is complete functional redundancy of the PI3K isoforms, necessitating multiple isoform inhibition to reverse GM-CSF-induced neutrophil survival. This finding informs our understanding of the mechanisms regulating neutrophil apoptosis and suggests neutrophil survival would be resilient to individual isoform-selective PI3K inhibitors.
    Preview · Article · Nov 2010 · Thorax

  • No preview · Conference Paper · Dec 2009