National University of Ireland, Maynooth

National University of Ireland, Maynooth
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Faculties & Departments

Department of Biology

Dr. Sinead Miggin, BSc, MSc, PhD (NUI)
Head of Laboratory

Immune Signalling Laboratory

 

Dr. Sinead MigginResearch Interests

My research focuses on the molecular mechanisms involved in regulating the innate immune system through the Toll-like receptors (TLRs).  TLRs play a critical role in the evolutionary conserved innate immune response and represents our first line of defense against invading pathogens.  TLRs are activated in response to a broad spectrum of pathogen-associated molecular patterns (PAMPs) ranging from bacterial and viral components to fungal and protozoal molecules. The capacity not only to respond appropriately but also to self-regulate host responses to invading pathogens is vital in our ability to mount an appropriate primary immune response. 

 

The TLRs mediate their actions via adaptor molecules of which there are five, namely MyD88, Tirap/Mal, Trif, TRAM and SARM.  Each of these molecules interacts heterophilically with defined TLRs. MyD88 is the central adapter molecules interacting with all TLRs except TLR3.  Upon ligand activation, MyD88 recruits members of the IRAK family and TRAF-6 eventually leading to activation of NF-kB and production of pro-inflammatory cytokines including IL-1beta, TNFalpha and IL-18.  This is termed the MyD88-dependent pathway.  The second adaptor molecule, Mal is thought to act as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.  Figure 2 shown the expression of Mal (depicted in green) on the cell surface of HEK293 cells. In addition, the TRIF-dependent pathway may also be activated, as is the case for TLR3 and TLR4.  Whereas Tram is thought to act as a bridging adaptor between Trif and TLR4, Trif interacts directly with TLR3.  Activated Trif recruits TBK1 and together with IKKi mediate interferon regulatory factor (IRF)3 phosphorylation, dimerisation and nuclear translocation leading to Type-1 interferon induction.  Trif also interacts with TRAF6 and receptor-interacting protein (RIP)-1 which mediate NF-kB activation.

Toll-like Receptor Signalling:

My group are interested in exploring the molecular architecture of the TLR and adaptor molecule complexes in response to various pathogens and to endogenous TLR ligands with the aim of identifying ligand-specific TLR complexes. My group are primarily interested in characterising TLR4, TLR2 and TLR3 signalling. My group are currently investigating some novel aspects to TLR3 signalling. I am interested in knowing how the Toll-like Receptors are regulated at the molecular level. Why are different TLRs activated by different ligands? Why do different TLRs selectively use different adaptor molecules?

Chronic Inflammation:

Chronic Inflammatory Diseases such as Rheumatoid Arthritis (RA), Osteoarthritis (OA) and Type 2 Diabetes, whilst having apparently unrelated aetiologies, share a common late stage pathogenic process, characterized by increases in pro-inflammatory cytokines, such as TNFa, IL-1b, IL-6 and IL-18. During chronic inflammatory episodes, the ‘in-born’ or innate immune system may become dysregulated through mechanisms involving Caspase-1 and Toll-like receptors (TLRs). We have recently shown that TLR2 and TLR4 signalling is modulated by cleavage of Mal by Caspase-1 (Miggin et al., PNAS). Given these findings, I am interested in exploring the molecular mechanisms involved in the pathogenesis of chronic inflammatory diseases. My group are particularly interested in investigating TLR signalling during RA and OA disease episodes following stimulation with endogenous and exogenous TLR ligands. My group are also exploring the role of TLRs in the pathogenesis of Type II Diabetes using biological samples from diabetic patients with good and poor glucose control. Overall, our research aims to develop our understanding of the molecular mechanisms involved in regulating Rheumatoid and Osteoarthritis and Type II Diabetes.

Laboratory Personnel

Graduate Students

  • Ashwini Maratha
  • Suaad Ahmed
  • Aisha Qasim Butt
  • Enda Shevlin

Clinical Collaborators

  • Professor Oliver Fitzgerald, Rheumatology Unit, St Vincent’s Hospital, Dublin
  • Dr Shu Hoashi, Endocrinology, Midlands Regional Hospital, Mullingar, Co. Westmeath 

Funding Sources

  • Health Research Board
  • Science Foundation Ireland
  • Departmental Funds

Publications

  • Aisha Qasim Butt and Sinead M. Miggin (2012) Cancer & Viruses: A Double-Edged Sword. Accepted for publication. Proteomics
  • Jakub Siednienko, Ashwini Maratha, Shuo Yang, Magorzata Mitkiewicz, Sinead M. Miggin* and Paul N. Moynagh*(2011) The NF-kB subunits RelB and cRel Negatively Regulate TLR3-mediated IFN-beta production via induction of the transcriptional repressor protein YY1. J Biol Chem. 286(52):44750-63 PMID: 22065573  *joint senior authorship
  • O'Hanlon KA, Cairns T, Stack D, Schrettl M, Bignell EM, Kavanagh K, Miggin SM, O'Keeffe G, Larsen TO, Doyle S. (2011) Targeted Disruption of Nonribosomal Peptide Synthetase pes3 Augments the Virulence of Aspergillus fumigatus. Infect Immun. 10:3978-92. PMID: 21746855
  • Siednienko J, Gajanayake T, Fitzgerald KA, Moynagh P, Miggin SM. (2011) Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-(beta) and RANTES production. J Immunol. 2011 Feb 15;186(4):2514-22. (1 citation). PMID: 21248248.
  • Jakub Siednienko, Annett Halle, Kamalpreet Nagpal, Douglas T. Golenbock and Sinéad M. Miggin. TLR3 mediated IFN-b gene induction is negatively regulated by the TLR adaptor Mal. (2010) Eur J Immunol. 40:3150-3160. DOI: 10.1002/eji.201040547
  • Sinead M. Miggin, Eva Palsson-McDermott, Aisling Dunne, Caroline Jefferies, Emmanuel Pinteaux, Caroline Murphy, Paul N. Moynagh, Masahiro Yamamoto, Shizuo Akira, Nancy Rothwell, Douglas T. Golenbock, Katherine A. Fitzgerald and Luke AJ O’Neill. NF-kappaB activation by MyD88 adapter-like is regulated by Caspase-1. (2007) Proc. Natl. Acad. Sci. 104: 3372-3377 (18 citations). PMID: 17360653
  • Miggin, S. M. and O’Neill, LA. New insights into the regulation of TLR signaling. (2006) J. Leukoc. Biol. 80(2):220-6 (40 citations)  **Listed as one of the top 10 most cited immunology papers in Ireland. Source: ISI Wed of Knowledge, 2008. PMID: 16698941
  • Wietek, C., Miggin, S. M., Jefferies, C. A. and O’Neill, L. A. Interferon regulatory factor-3-mediated activation of the interferon-sensitive response element by Toll-like receptor (TLR) 4 but not TLR3 requires the p65 subunit of NF-kappaB. J. Biol. Chem. (2003) 278: 50923-50931 (48 citations). PMID: 14557267
  • Miggin, S. M., Lawler, O. A. and Kinsella, B. T. Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J. Biol. Chem. (2003) 278: 6947-6958 (17 citations). PMID: 12488443
  • Miggin, S. M. and Kinsella, B. T. Investigation of the mechanisms of G protein : effector coupling by the human and mouse prostacyclin receptors;  identification of critical species-dependent differences. J. Biol. Chem. (2002) 277: 27053-27064 (20 citations). PMID: 12016224
  • Miggin, S. M. and Kinsella, B. T. Regulation of the extracellular signal regulated protein kinase cascades by the alpha and beta isoforms of the human thromboxane A2 receptor. Mol. Pharmacol. (2002) 61: 817-831 (22 citations). PMID: 11901221
  • Miggin, S. M., Lawler, O. A. and Kinsella, B. T. Investigation of a functional requirement for isoprenylation by the human prostacyclin receptor. Eur. J. Biochem. (2002) 269: 1714-1725 (16 citations). PMID: 11895442
  • Miggin, S. M., Coyle, A. T., and Kinsella B. T. Characterization of the 5' untranslated region of alpha and beta isoforms of the human thromboxane A2 receptor (TP). Differential promoter utilization by the TP isoforms. Eur. J. Biochem. 2002 Aug;269(16):4058-73. (9 citations). PMID: 12180983
  • Lawler, O. A., Miggin, S. M. and Kinsella, B. T. The effects of the statins lovastatin and cerivastatin on signalling by the prostanoid IP-receptor. Br. J. Pharmacol. (2001) 132:1639-49 (14 citations). PMID: 11309234
  • Miggin, S. M. and Kinsella, B. T. Thromboxane A2 receptor mediated activation of the mitogen activated protein kinase cascades in human uterine smooth muscle cells. Biochimica et Biophysica Acta. (2001) 1539: 147-162 (35 citations). PMID: 11389977
  • Lawler, O. A., Miggin, S. M. and Kinsella, B. T. Protein kinase A dependent phosphorylation of serine 357 of the mouse prostacyclin receptor regulated its coupling to Gs-, Gi- and to Gq- coupled effector signalling. J. Biol. Chem. (2001) 276: 33596-33607 (62 citations). PMID: 11443126
  • Miggin, S. M. and Kinsella, B. T. Expression and tissue distribution of the mRNAs encoding the human thromboxane A2 receptor (TP) alpha and beta isoforms. Biochim Biophys Acta. (1998) 27:543-59.  (46 citations). PMID: 9838218

Book Chapters:

  • Enda Shevlin and Sinead Miggin (2011) Toll-like receptor adaptor protein. Encyclopedia of Signaling Molecules. Ed, Choi, S. Springer Reference ISBN: 978-1-4419-0461-4
  • Aisha Q. Butt and Sinead M Miggin (2011) Toll-like receptor 3. Encyclopedia of Signaling Molecules. Ed, Choi, S. Springer Reference ISBN: 978-1-4419-0461-4
  • Jakub Siednienko and Sinead M. Miggin. Expression Analysis of the Toll-Like Receptors in Human Peripheral Blood Mononuclear Cells. In: Methods in Molecular Biology, Vol. 517 McCoy, Claire E.; O'Neill, Luke A.J. (Eds.) (2009). ISBN: 978-1-934115-72-5. 517:3-14.PMID: 19378036
Last edited: Wednesday, 04-Apr-2012 11:58:12 IST

Biology Department , NUI Maynooth
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