English

Abstract

Introduction Inflammation is triggered when innate immune cells detect microbial infection or tissue damage. Surveillance mecha­ nisms involve pattern recognition receptors on the cell surface and in the cytoplasm. Most pattern recognition receptors respond to pathogen­ associated molecular patterns or host­derived damage­associated mole­ cular patterns by triggering activation of various transcription factors. Induction of cytokines promotes the activation and recruitment of leukocytes, which are critical for elim­ inating pathogens and host debris. In order to avoid immunopathology, the system is very tightly regulated by numerous molecules that limit the magnitude and duration of the inflammatory response. In this review we present current knowledge on pathogen recognition through diff­ erent pattern recognition receptors and the complex signalling pathways responsible for activation of inflam­ matory and antimicrobial responses. Conclusion There are still many unresolved questions, such as the exact nature of the molecular events leading to diff­ erent immune receptor activation and also identity of some unknown ligands for the receptors. Unravelling of these will offer insight into what critical components might be target­ ed for better therapeutic benefits in inflammatory disorders. Introduction The role of inflammatory response is to combat infection and tissue injury. The innate immune system constitutes the first line of host defence during infection and therefore plays a very crucial role in the early recognition and subsequent trigger­ ing of a pro-inflammatory response to invading pathogens1. The adaptive immune system, on the other hand, is responsible for elimination of pathogens during the late phase of infection and in the generation of immunological memory. The innate immune response is mediated pri­ marily by phagocytic cells and antigen­presenting cells (APCs), such as macrophages, and dendritic cells (DCs), and has been regarded as relatively non-specific2, whereas the adaptive immune response is charac­ terized by antigen-specific receptors on lymphocytes generated by clonal gene rearrangements. Innate immune cells of tissues such as macrophages, fibroblasts and dendritic cells, as well as circulating leukocytes, recognize pathogen inva­ sion or cellular damage with pattern recognition receptors (PRRs). These receptors detect pathogen­associated molecular patterns (PAMPs), such as pathogen­derived nucleic acids and cell wall components, fungal β-glucan, bacterial flagellin, and lipopolysaccharide (LPS) from Gram­ negative bacteria. PRRs also recog­ nize damage­associated molecular patterns (DAMPs), released from injured cells during apoptosis or necrosis. DAMPs include uric acid, ATP, and the DNA­binding nuclear protein HMGB1 and amyloid β fibrils. Activated PRRs then initiate signal­ ling cascades to trigger the release of factors that promote recruitment of leukocytes to the infected region. In this review, we look into the inflammatory signalling response emanating from the recognition of microbial infection and cellular injury by PRRs. Among PRRs, membrane­bound toll­like receptors (TLRs) play a cen­ tral role in the initiation of immune response against pathogen invasion. However, other PRRs are also involved—including membrane­bound C­type lectin receptors (CLRs), cyto­ solic proteins such as NOD­like recep­ tors (NLRs) and RIG­I­like receptors (RLRs). Among these receptor types, TLRs and RLRs are primarily important for the production of type I interfer­ ons (IFNs), whereas NLRs are known to regulate interleukin-1β (IL-1β) production through activation of caspase­1. Discussion Toll-like receptors TLRs were the first PRRs to be iden­ tified. They are also the most well characterized and recognize a wide range of PAMPs3–5. TLRs are trans­ membrane proteins which comprise an ectodomain, which contains leucine­rich repeats that mediate the recognition of PAMPs, a transmem­ brane region, and cytosolic Toll­IL­1 receptor (TIR) domains that activate downstream signalling pathways. TLRs are expressed either on the cell surface or on intracellular vesicles. To date, 10 and 12 functional TLRs have been identified in human and mice, respectively. Each TLR detects distinct PAMPs from bacteria, viruses, fungi and parasites. Upon recognition of respective PAMPs, TLRs recruit a specific set of adaptor molecules that have TIR doma ins, such as MyD88 and TRIF, and initiate downstream signalling