Introduction
Inflammation is a protective response by the body to ensure removal of detrimental stimuli, as well as a healing process for repairing damaged tissue (Medzhitov, 2008). Inflammation is caused by various factors such as microbial infection, tissue injury, and cardiac infarction. Classically, inflammation is characterized by five symptoms: redness, swelling, heat, pain, and loss of tissue function.
These macroscopic symptoms reflect increased permeability of the vascular endothelium allowing leakage of serum components and extravasation of immune cells. The inflammatory response is then rapidly terminated and damaged tissues are repaired. However, overproduction of cytokines (a cytokine storm) by immune cells to overwhelm pathogens can be fatal. A cytokine storm can also be caused by noninfectious diseases such as graft-versus-host disease (GVHD).
extravasation : 혈관외유출 (血管外遊出, 영어: extravasation )은 체액이 들어 있는 공간에서 주변으로, 특히
혈관으로부터 혈액이나 혈구가 유출되는 현상이다. 관외유출(管外遊出), 유출(遊出)이라고도 한다. 염증의 경우, 이는 백혈구가 모세혈관 벽을 통해 주변 조직으로 이동하는 것을 말한다. 이는 백혈구 혈관외유출이라고 하며, 혈구누출이라고도 한다.
Inflammatory responses are also critical for the pathogenesis of autoimmune diseases. The innate immune system is the major contributor to acute inflammation induced by microbial infection or tissue damage (Akira et al., 2006; Beutler et al., 2006).
Furthermore, innate immunity is also important for the activation of acquired immunity. Although innate immune cells including macrophages and dendritic cells (DCs) play important roles, nonprofessional cells such as epithelial cells, endothelial cells, and fibroblasts also contribute to innate immunity.
Germline-encoded pattern recognition receptors (PRRs) are responsible for sensing the presence of microorganisms. They do this by recognizing structures conserved among microbial species, which are called pathogen-associated molecular patterns (PAMPs). Recent evidence indicates that PRRs are also responsible for recognizing endogenous molecules released from damaged cells, termed damageassociated molecular patterns (DAMPs).
Currently, four different classes of PRR families have been identified. These families include transmembrane proteins such as the Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), as well as cytoplasmic proteins such as the Retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) and NOD-like receptors (NLRs).
These PRRs are expressed not only in macrophages and DCs but also in various nonprofessional immune cells. With the exception of some NLRs, the sensing of PAMPs or DAMPs by PRRs upregulates the transcription of genes involved in inflammatory responses.
These genes encode proinflammatory cytokines, type I interferons (IFNs), chemokines and antimicrobial proteins, proteins involved in the modulation of PRR signaling, and many uncharacterized proteins. The expression patterns of the inducible genes differ among activated PRRs. The inflammatory response is orchestrated by proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6.
These cytokines are pleiotropic proteins that regulate the cell death of inflammatory tissues, modify vascular endothelial permeability, recruit blood cells to inflamed tissues, and induce the production of acute-phase proteins.
pleiotropic : 하나의 유전자는 두 개 이상의 phenotype trait에 영향을 미치는 것을 의미
Although TNF and IL-6 are mainly regulated at the transcriptional and translational levels, the production of IL-1b is regulated by a two-step mechanism. The first step is the expression of an IL-1b zymogen, pro-IL-1b, which is regulated by the synthesis of its mRNA in a TLR signal-dependent manner. However, IL-1b maturation requires cleavage of pro-IL-1b by a protease, caspase-1, which is activated independently of TLR signaling.
The complex that activates caspase-1, called the inflammasome, is composed of NLRs, ASC, and caspase-1 (see Review by K. Schroder and J. Tschopp on page 821 of this issue).
Type I IFNs, including multiple forms of IFN-a and single forms of IFN-b, IFN-u, etc., are also involved in the modulation of inflammation (Honda et al., 2006). Type I IFNs play central roles in antiviral responses by inducing apoptotic cell death in virally infected cells, rendering cells resistant to virus infection, activating acquired immunity, and stimulating hematopoietic stem cell turnover and proliferation.
Secreted type I IFNs alert the surrounding cells via type I IFN receptors by triggering a signaling cascade that leads to the phosphorylation and nuclear translocation of IFN-stimulated gene factor 3 (ISGF3), a complex composed of Signal Transducers and Activators of Transcription 1 (STAT1), STAT2, and IFN-regulatory factor (IRF) 9.
ISGF3 induces expression of IFN-inducible antiviral genes such as protein kinase R (PKR) and 20 50 -oligoadenylate synthase (OAS) among others. PKR suppresses the proliferation of virus-infected cells and 20 50 -OAS activates RNase L, which cleaves viral nucleotides in order to inhibit virus replication. In this Review, we discuss how distinct PRRs (with particular emphasis on TLRs and RLRs) sense the presence of pathogens and cellular insults and the mechanisms by which these PRR signals elicit inflammation.