PhD Student, Queen's University Belfast
Investigating novel roles for SOCS proteins during inflammation.
The innate immune system, which forms the first line of defence from the external environment, induces inflammation in response to injury or infection. Macrophages, an innate immune cell, are recruited by signals released from the site of injury or infection. Once at the site, macrophages orchestrate the immune response tailored to the type of infection and injury enabling resolution and restoration of homeostasis.
Inflammasomes represent innate immune signalling complexes that play a vital role in the induction of inflammation and wound healing. They are activated within macrophages upon detection of infection or injury. This leads to secretion of inflammatory cytokines enabling recruitment of more immune cells and the establishment of a greater immune response.
Unfortunately, when inflammasome activity is dysregulated this can lead to recurrent attacks of fever with systemic inflammation. As existing therapies are often unsuccessful in patients with dysregulated inflammasome activity, current research has focused on understanding the regulation of inflammasome activity to identify novel targets or signalling pathways that can be modulated in patients to relieve symptoms.
Recently, post-translational modifications have been identified to play an important role in regulating inflammasome activity, in particular the process of ubiquitination (enables targeting of proteins for degradation, and activation). Therefore, it is of great value to identify E3 ligases (enable ubiquitination) or complexes that may regulate ubiquitination of inflammasome components.
My research investigates the role of the E3 ubiquitin ligases suppressor of cytokine signalling (SOCS) proteins in regulating inflammasome activity in response to inflammatory stimuli, such as bacterial infection.
To accomplish this I utilise various SOCS-deficient mouse models that allow me to characterise the effects of SOCS2 and SOCS3 deficiencies in inflammation and infection.
In the future this knowledge will enable us to informatively target specific aspects of inflammatory pathways and infection to treat disease and clear infection.
Abstract: Cytokines regulate the growth and differentiation of cells by binding to cell-surface receptors and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Cytokine signaling is negatively regulated with respect to both magnitude and duration, and it is now clear that the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS) contributes significantly to this process. Transcripts encoding CIS, SOCS1, SOCS2, and SOCS3 are upregulated in response to cytokine stimulation, and the corresponding SOCS proteins inhibit cytokine-induced signaling pathways. SOCS proteins therefore form part of a classical negative feedback circuit. SOCS family members modulate signaling by several mechanisms, which include inactivation of the Janus kinases (JAKs), blocking access of the signal transducers and activators of transcription (STATs) to receptor binding sites, and ubiquitination of signaling proteins and their subsequent targeting to the proteasome. Gene targeting has been used to generate mice lacking socs1, socs2, or socs3, in order to elucidate the physiological function of these SOCS family members. The analysis of socs1(-/-) mice has revealed that SOCS1 plays a key role in the negative regulation of interferon-gamma signaling and in T cell differentiation. Socs2(-/-) mice are 30%-40% larger than wild-type mice, demonstrating that SOCS2 is a critical regulator of postnatal growth. Additionally, the study of embryos lacking socs3 has revealed that SOCS3 is an important regulator of fetal liver hematopoiesis. The biological role of other SOCS proteins remains to be determined.
Pub.: 13 Sep '01, Pinned: 07 Oct '17
Abstract: The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.
Pub.: 17 Feb '15, Pinned: 06 Sep '17
Abstract: Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. In this Review, we discuss the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and we highlight the similarities to another molecular signalling platform - the apoptosome - that monitors cellular health. Extracellular regulatory mechanisms are discussed, as well as the intracellular control of inflammasome assembly, for example, via ion fluxes, free radicals and autophagy.
Pub.: 25 May '13, Pinned: 31 Aug '17
Abstract: Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway. Here we use mice unable to express SOCS-2 to examine its function in vivo. SOCS-2(-/-) mice grew significantly larger than their wild-type littermates. Increased body weight became evident after weaning and was associated with significantly increased long bone lengths and the proportionate enlargement of most organs. Characteristics of deregulated growth hormone and insulin-like growth factor-I (IGF-I) signalling, including decreased production of major urinary protein, increased local IGF-I production, and collagen accumulation in the dermis, were observed in SOCS-2-deficient mice, indicating that SOCS-2 may have an essential negative regulatory role in the growth hormone/IGF-I pathway.
Pub.: 13 Jul '00, Pinned: 31 Aug '17
Abstract: Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors (PRRs), including Toll-like receptors (TLR), inflammasome, and nucleotide oligomerization domain (NOD). The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKβ, mTOR/S6 kinase, and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that PRRs and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance.
Pub.: 15 Jan '13, Pinned: 31 Aug '17
Abstract: Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene transcriptional regulation, but their signals must be attenuated by multiple mechanisms. These include the suppressors of cytokine signaling (SOCS) family of proteins, which represent a main negative regulation mechanism for the JAK-STAT pathway. Cytokine-inducible Src homology 2 (SH2)-containing protein (CIS), SOCS1, and SOCS3 proteins regulate cytokine signals that control the polarization of CD4(+) T cells and the maturation of CD8(+) T cells. SOCS proteins also regulate innate immune cells and are involved in tumorigenesis. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in T cells and tumor immunity.
Pub.: 19 Jul '17, Pinned: 31 Aug '17
Abstract: The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. They have been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research.
Pub.: 30 Jun '15, Pinned: 31 Aug '17
Abstract: The covalent attachment of ubiquitin to target proteins is one of the most prevalent post-translational modifications, regulating a myriad of cellular processes including cell growth, survival, and metabolism. Recently a novel RING E3 ligase complex was described termed LUBAC (Linear Ubiquitin Assembly Complex), which is capable of connecting ubiquitin molecules in a novel head-to-tail fashion via the N-terminal methionine residue. LUBAC is a heteromeric complex composed of HOIL-1 (Heme-Oxidized Iron responsive element binding protein 2 ubiquitin Ligase-1), HOIP (HOIL-1-Interacting Protein), and SHARPIN (Shank-Associated RH domain-Interacting Protein). The essential role of LUBAC-generated linear chains for activation of NF-κB signaling was first described in the activation of TNF-α-receptor signaling complex. A decade of research has identified additional pathways that utilize LUBAC for downstream signaling, including CD40 ligand and the IL-1β receptor as well as cytosolic pattern recognition receptors including NOD2, RIG-I and the NLRP3 inflammasome. Even though the three components of the complex are required for full activation of NF-κB, the individual components of LUBAC regulate specific cell type and stimuli dependent effects. In humans, autosomal defects in LUBAC are associated with both autoinflammation and immunodeficiency with additional disorders described in mice. Moreover, in the lung epithelium, HOIL-1L ubiquitinates target proteins independently of the other LUBAC components, providing another layer of complexity to the function and regulation of LUBAC.
Pub.: 06 Feb '16, Pinned: 31 Aug '17