Mini review
Pattern recognition receptors—Molecular orchestrators of inflammation in inflammatory bowel disease

https://doi.org/10.1016/j.cytogfr.2012.09.003Get rights and content

Abstract

Pattern recognition receptors (PRRs) are a family of germline encoded receptors responsible for the detection of “pathogen associated molecular patterns” (PAMPs) or host derived “damage associated molecular patterns” (DAMPs) which induce innate immune signalling to generate a pro-inflammatory profile within the host. Four main classes of PRRs are recognised, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs) and C-type lectin receptors (CLRs). Abnormal activation of PRRs has been implicated in various autoimmune and inflammatory conditions including rheumatoid arthritis and asthma. Recent growing evidence has implicated these PRRs as contributory elements to the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Here, the current literature which implicates PRRs in IBD and CAC is comprehensively reviewed.

Introduction

The human intestine is a complex ecological environment which harbours an estimated 1010–1012 microbial cells CFU/ml in the colon [1]. PRRs represent a group of germline encoded receptors responsible for the detection of conserved microbial PAMPs, including bacterial and fungal cell wall components and viral nucleic acids as well as maintaining gut homeostasis [2]. PRRs also respond to endogenously derived molecules released from damaged cells, known as DAMPs. The mammalian immune system has evolved to contain two mechanistically distinct, yet functionally similar arms, namely the immediate, non-clonally derived innate immune system which recognises a multitude of foreign antigens and the temporally delayed yet highly specific adaptive immune system [1]. Innate immunity is based on the fundamental concept of the recognition of conserved bacterial motifs, PAMPs, as non-self-entities in vivo, by PRRs whose activation generally results in the up-regulation at the transcriptional level of inflammatory genes and subsequent clearance of the pathogen [2]. Aberrant recognition of commensal microbiota as foreign by this innate mechanism is now believed to be one of the main contributory factors to the persistently activated innate inflammatory response observed in IBD and associated gastrointestinal malignancies [3], [4], [5]. The purpose of this review is to comprehensively delineate the molecular signalling pathways of PRRs, which have been implicated so far in the pathogenesis of both human and experimental IBD and CAC and to discuss their potential therapeutic modulation. Table 1 summarises the four main classes of PRRs, their members, biological function, activating ligands and any known associations with IBD and CAC.

Section snippets

Inflammatory bowel disease (IBD) and colitis-associated cancer (CAC)

Crohn's disease (CD) and ulcerative colitis (UC) are chronic, relapsing immune mediated disorders of the gastrointestinal tract (GIT) encompassed under the title of IBD. Disease presentation generally occurs early in life between ages 15 and 30 years, mainly in countries which have adopted a Westernized lifestyle such as North America and Europe. Chronic, remittent-relapsing intestinal inflammation is the hallmark of IBD often resulting in the clinical presentation of abdominal pain, fever,

Toll-like receptors (TLRs)

TLRs are a class of functional, type-I transmembrane glycoproteins expressed by a wide spectrum of cells ranging from myelomonocytic cells to endothelial and epithelial cells (Fig. 2). Thus far 10 functional TLRs, subcategorized based on cellular location, have been discovered in humans (12 in mice), which recognise microbial PAMPs and host derived DAMPs to initiate an inflammatory response [13]. TLR1/2/4/5/6 are expressed on the surface of innate cells such as dendritic cells (DCs),

Concluding remarks and future perspectives

In summary, there is a growing body of evidence which implicates dysregulated PRR signalling as a strong contributor to the multifactorial conditions, IBD and CAC. It should however be noted that, to date much of the investigations have been conducted on murine models of experimental colitis, a fact which may limit the application of this data to human studies. The PRRs’ contribution to the innate immune response is well acknowledged; however, their contribution to adaptive immune responses and

Acknowledgements

The authors would like to thank Dr. Ken Nally, Alimentary Pharmabiotic Centre, University College Cork (UCC) for his critical expertise regarding Fig. 3, Fig. 4. The Pharmacodelivery Group, School of Pharmacy, UCC is funded by a Science Foundation Ireland (SFI) strategic research cluster grant no: 07/SRC/B1154. The Alimentary Pharmabiotic Centre is a research center funded by Science Foundation Ireland (SFI) and supported by SFI grants 02/CE/B124 and 07/CE/B1368.

David Walsh received his B.Sc. in pharmacy from the Cavanagh School of Pharmacy, University College Cork, Ireland. Presently, he works as a research assistant in the laboratory of Professor Caitriona O’Driscoll at University College Cork (UCC) where his project includes investigating the use of modified β-cyclodextrin derivatives for the non-viral delivery of siRNA in an acute-colitis mouse model of inflammatory bowel disease (IBD). Following the successful completion of his forthcoming MPharm

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    David Walsh received his B.Sc. in pharmacy from the Cavanagh School of Pharmacy, University College Cork, Ireland. Presently, he works as a research assistant in the laboratory of Professor Caitriona O’Driscoll at University College Cork (UCC) where his project includes investigating the use of modified β-cyclodextrin derivatives for the non-viral delivery of siRNA in an acute-colitis mouse model of inflammatory bowel disease (IBD). Following the successful completion of his forthcoming MPharm degree, he hopes to pursue his Ph.D. qualification. His research interests include IBD, cancer and the therapeutic modulation of cell signalling pathways.

    Dr. Joanna McCarthy is a post-doctoral research scientist at University College Cork (UCC). After completing her B.Sc. (genetics) in 2005 from UCC, she was awarded a research internship at the Institute of Molecular Medicine for the Prevention of Human Diseases in Houston-Texas, under the supervision of Dr. Murad (1998 Nobel laureate). In 2006, she worked as a R&D scientist at the in vitro medical device company Trinity Biotech plc. working on diagnostic HIV devices. In 2010, she defended her Ph.D. in pharmacology at Trinity College Dublin. Her research interests include; nanoparticles, pulmonary nanomedicine, non-viral delivery of siRNA for IBD and cancer.

    Professor Caitriona O’Driscoll received her B.Sc. in pharmacy from University College Dublin in 1976 and a Ph.D. in pharmaceutics in 1983 from the University of Dublin, Trinity College. In 1977 she joined the faculty of the School of Pharmacy in Trinity College. In 2003 she was appointed professor of pharmaceutics at University College Cork and became the first Head of the School of Pharmacy, University College Cork. Her research interests include non-viral gene delivery, cyclodextrins, siRNA, IBD, cancer and Huntington's disease.

    Dr. Silvia Melgar received her B.Sc. in molecular biology and a Ph.D. in immunology from Umeå University, Sweden. In 2002, she joined AstraZeneca R&D, Sweden, as a post-doctoral fellow and later became senior research scientist in the IBD in vivo pharmacology group. In 2008, she joined GlaxoSmithKline (GSK) as principal scientist and was based in the Alimentary Pharmabiotic Centre (APC) at University College Cork under the GSK-APC collaboration. She has been an investigator in the APC, UCC since 2008, and became Senior Research Fellow in 2012. Her research interests include the effect of environmental factors e.g. diet in host–bacterial interactions in IBD and colitis-associated cancer, epithelial cell and innate immune cell responses to commensal/pathogenic bacteria.

    1

    SM and COD share joint senior authorship of this work.

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