Protease signaling to G protein-coupled receptors: implications for inflammation and pain

Proteases, like thrombin, trypsin, cathepsins, or tryptase, can signal to cells by cleaving in a specific manner, a family of G protein-coupled receptors, the protease-activated receptors (PARs). Proteases cleave the extracellular N-terminal domain of PARs to reveal tethered ligand domains that bind to and activate the receptors. Recent evidence has supported the involvement of PARs in inflammation and pain. Activation of PAR(1), PAR(2), and PAR(4) either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Recent studies suggest a crucial role for the different PARs in innate immune response. The role of PARs in the activation of pain pathways appears to be dual. Subinflammatory doses of PAR(2) agonists induce hyperalgesia and allodynia, and PAR(2) activation has been implicated in the generation of inflammatory hyperalgesia. In contrast, subinflammatory doses of PAR(1) or PAR(4) increase nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as analgesic mediators. PARs have to be considered as an additional subclass of G protein-coupled receptors that are active participants to inflammation and pain responses and that could constitute potential novel therapeutic targets.     

Protease Signaling to G Protein-Coupled Receptors: Implications for Inflammation and Pain

Proteases, like thrombin, trypsin, cathepsins, or tryptase, can signal to cells by cleaving in a specific manner, a family of G protein-coupled receptors, the protease-activated receptors (PARs). Proteases cleave the extracellular N-terminal domain of PARs to reveal tethered ligand domains that bind to and activate the receptors. Recent evidence has supported the involvement of PARs in inflammation and pain. Activation of PAR₁, PAR₂, and PAR₄ either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Recent studies suggest a crucial role for the different PARs in innate immune response. The role of PARs in the activation of pain pathways appears to be dual. Subinflammatory doses of PAR₂ agonists induce hyperalgesia and allodynia, and PAR₂ activation has been implicated in the generation of inflammatory hyperalgesia. In contrast, subinflammatory doses of PAR₁ or PAR₄ increase nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as analgesic mediators. PARs have to be considered as an additional subclass of G protein-coupled receptors that are active participants to inflammation and pain responses and that could constitute potential novel therapeutic targets.     

TLRs and chronic inflammation

After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases. In this review, an overview of the currently known TLRs and their signaling pathways is given and reports about their expression and activation in chronic inflammatory diseases are recapitulated.     

New insights into TRP channels: Interaction with pattern recognition receptors

An increasing number of studies have implicated that the activation of innate immune system and inflammatory mechanisms are of importance in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms in response to pathogens or tissue injury, which is performed via germ-line encoded pattern-recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) or dangers-associated molecular patterns (DAMPs). Intracellular pathways linking immune and inflammatory response to ion channel expression and function have been recently identified. Among ion channels, transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes. In this review, we summarize current knowledge about classifications, functions, and interactions of TRP channels and PRRs, which may provide new insights into their roles in the pathogenesis of inflammatory diseases.     

食源性致病菌激活NLRP3炎症小体及食源性功能物质的抑制机理研究进展

食源性致病菌感染是引起食源性疾病的首要因素,严重影响人类健康。炎症小体通过识别受体感知入侵宿主的危险信号进而组装形成多聚蛋白复合物,从而诱导炎症反应,是先天免疫系统中识别食源性病原菌感染和清除病原体的重要防线。NLRP3炎症小体是位于胞内的炎症反应平台,可以感知多种病原微生物的侵袭,在先天性免疫反应中起着至关重要的作用。食源性致病菌感染常引起NLRP3炎症小体的异常激活,介导多种炎症性疾病的发生和发展,因此,许多抗炎研究中常常以NLRP3炎症小体作为靶点。本文总结了食源性致病菌及其代谢产物激活NLRP3炎症小体的分子机制,以及天然产物和膳食功能物质抑制NLRP3炎症小体激活的机理,为治疗炎症性疾病、开发缓解致病菌诱导的炎症反应的功能化合物提供新的思路。     

Innate recognition of microbial-derived signals in immunity and inflammation

Microbes generate a vast array of different types of conserved structural components called pathogen-associated molecular patterns(PAMPs),which canbe recognized by cells of the innate immune system.This recognition of "nonself" signatures occurs through host pattern recognition receptors(PRRs),suggesting that microbial-derived signals are good targets for innate immunity to discriminate between self- and nonself.Such PAMP-PRR interactions trigger multiple but distinct downstream signaling cascades,subsequently leading to production of proinflammatory cytokines and interferons that tailor immune responses to particular microbes.Aberrant PRR signals have been associated with various inflammatory diseases and fine regulation of PRR signaling is essential for avoiding excessive inflammatory immune responses and maintaining immune homeostasis.In this review we summarize the ligands and signal transduction pathways of PRRs and highlight recent progress of the mechanisms involved in microbe-specific innate immune recognition during immune responses and inflammation,which may provide new targets for therapeutic intervention to the inflammatory disorders.     

Invariant natural killer T cells: bridging innate and adaptive immunity

Cells of the innate immune system interact with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptive immune system recognize pathogens through diverse, antigen-specific receptors that are generated by somatic DNA rearrangement. Invariant natural killer T (iNKT) cells are a subset of lymphocytes that bridge the innate and adaptive immune systems. Although iNKT cells express T cell receptors that are generated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limited set of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innate immune system. Functionally, iNKT cells most closely resemble cells of the innate immune system, as they rapidly elicit their effector functions following activation, and fail to develop immunological memory. iNKT cells can become activated in response to a variety of stimuli and participate in the regulation of various immune responses. Activated iNKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response. A variety of glycolipid antigens that can differentially elicit distinct effector functions in iNKT cells have been identified. These reagents have been employed to test the hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases. Here, we review the innate-like properties and functions of iNKT cells and discuss their interactions with other cell types of the immune system.     

Salmonella Typhimurium Type III Secretion Effectors Stimulate Innate Immune Responses in Cultured Epithelial Cells

Recognition of conserved bacterial products by innate immune receptors leads to inflammatory responses that control pathogen spread but that can also result in pathology. Intestinal epithelial cells are exposed to bacterial products and therefore must prevent signaling through innate immune receptors to avoid pathology. However, enteric pathogens are able to stimulate intestinal inflammation. We show here that the enteric pathogen Salmonella Typhimurium can stimulate innate immune responses in cultured epithelial cells by mechanisms that do not involve receptors of the innate immune system. Instead, S. Typhimurium stimulates these responses by delivering through its type III secretion system the bacterial effector proteins SopE, SopE2, and SopB, which in a redundant fashion stimulate Rho-family GTPases leading to the activation of mitogen-activated protein (MAP) kinase and NF-κB signaling. These observations have implications for the understanding of the mechanisms by which Salmonella Typhimurium induces intestinal inflammation as well as other intestinal inflammatory pathologies.     

Recent insights into the role of the innate immune system in the development of alcoholic liver disease

The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of alcoholic liver disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of disease is by disrupting the signal transduction cascades mediating the innate immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogen-activated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of alcoholic liver disease.     

The role of IL-15 in gastrointestinal diseases: A bridge between innate and adaptive immune response

IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells.IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an ‘immunological niche’, in which immune response, inflammation and local homeostasis are modulated.Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases.     

The role of lipins in innate immunity and inflammation

Lipins are phosphatidic acid phosphatase enzymes whose cellular function in regulating lipid metabolism has been known for decades, particularly in metabolically active tissues such as adipose tissue or liver. In recent years evidence is accumulating for key regulatory roles of the lipin family in innate immune cells. Lipins may help regulate signaling through relevant immune receptors such as Toll-like receptors, and are also integral part of the cellular machinery for lipid storage in these cells, thereby modulating certain inflammatory processes. Mutations in genes that encode for members of this family produce autoinflammatory hereditary diseases or diseases with an important inflammatory component in humans. In this review we summarize recent findings on the role of lipins in cells of the innate immune system and in the onset and progress of inflammatory processes.     

Immunomodulatory functions of type I interferons

Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.     

Proteomic analysis of the LPS-induced stress response in rat chondrocytes reveals induction of innate immune response components in articular cartilage.

Activation of toll-like receptors (TLR) in articular chondrocytes has been reported to increase the catabolic compartment, leading to matrix degradation, while the main consequence of TLR activation in monocytic cells is the expression and secretion of components of the innate immune response, particularly that of inflammatory cytokines. The objective of the work reported here was to obtain a more complete picture of the response repertoire of articular chondrocytes to TLR activation. Mass spectrometry was used to analyse the secretome of stimulated and unstimulated cells. Characterization of TLR expression in rat articular chondrocytes by RT/PCR indicated that TLR4 was the major receptor form. Exposure of these cells to lipopolysaccharide (LPS), the well-characterized TLR4 ligand, induced production not only of the matrix metalloproteinases MMP3 and 13, but also of components traditionally associated with the innate immune response, such as the complement components C1r, C3 and complement factor B, long pentraxin-3 and osteoglycin. Neither TNF-alpha nor IL-1 was detectable in culture media following exposure to LPS. One of the most prominently-induced proteins was the chitinase-like protein, Chi3L1, linking its expression to the innate immune response repertoire of articular chondrocytes. In intact femoral heads, LPS induced expression of Chi3L1 in chondrocytes close to the articular surface, suggesting that only these cells mount a stress response to LPS. Thus articular chondrocytes have a capacity to respond to TLR activation, which results in the expression of matrix metalloproteases as well as subsets of components of the innate immune response without significant increases in the production of inflammatory cytokines. This could influence the erosive processes leading to cartilage degeneration as well as the repair of damaged matrix.     

Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms

Cardiovascular diseases are the human diseases with the highest death rate and atherosclerosis is one of the major underlying causes of cardiovascular diseases. Inflammatory and innate immune mechanisms, employing monocytes, innate receptors, innate cytokines, or chemokines are suggested to be involved in atherogenesis. Among the inflammatory pathways the cytokines are central players. Plasma levels of cytokines and related proteins, such as CRP, have been investigated in cardiovascular patients, tissue mRNA expression was analyzed and correlations to vascular diseases established. Consistent with these findings the generation of cytokine-deficient animals has provided direct evidence for a role of cytokines in atherosclerosis. In vitro cell culture experiments further support the suggestion that cytokines and other innate mechanisms contribute to atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs), including the endotoxin receptor TLR4. On the other hand, innate cytokines, such as IL-1 or TNF, or even autoimmune triggers may activate the cells. Cytokines potently activate multiple functions relevant to maintain or spoil homeostasis within the vessel wall. Vascular cells, not least smooth muscle cells, can actively contribute to the inflammatory cytokine-dependent network in the blood vessel wall by: (i) production of cytokines; (ii) response to these potent cell activators; and (iii) cytokine-mediated interaction with invading cells, such as monocytes, T-cells, or mast cells. Activation of these pathways results in accumulation of cells and increased LDL- and ECM-deposition which may serve as an 'immunovascular memory' resulting in an ever-growing response to subsequent invasions. Thus, vascular cells may potently contribute to the inflammatory pathways involved in development and acceleration of atherosclerosis.     

Toll-like receptors are key participants in innate immune responses

During an infection, one of the principal challenges for the host is to detect the pathogen and activate a rapid defensive response. The Toll-like family of receptors (TLRs), among other pattern recognition receptors (PRR), performs this detection process in vertebrate and invertebrate organisms. These type I transmembrane receptors identify microbial conserved structures or pathogen-associated molecular patterns (PAMPs). Recognition of microbial components by TLRs initiates signaling transduction pathways that induce gene expression. These gene products regulate innate immune responses and further develop an antigen-specific acquired immunity. TLR signaling pathways are regulated by intracellular adaptor molecules, such as MyD88, TIRAP/Mal, between others that provide specificity of individual TLR- mediated signaling pathways. TLR-mediated activation of innate immunity is involved not only in host defense against pathogens but also in immune disorders. The involvement of TLR-mediated pathways in auto-immune and inflammatory diseases is described in this review article.     

NOD1和NOD2：介导天然免疫的两种胞浆蛋白

NOD1和NOD2是新发现的一类参与天然免疫的胞浆蛋白质家族—核苷酸结合寡聚域样受体（the nucleotide bindingolig omerization domain-like receptor,NLRs）中的两个重要蛋白受体,它们通过识别外源病原菌的模式抗原分子而激活NF-κB等核转录因子,启动相关细胞因子的基因表达,释放炎性因子和抗菌肽等,其介导的信号通路在宿主抵御病原体感染的天然免疫中发挥着重要作用。     

Antiviral signaling through pattern recognition receptors

Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response.     

炎症小体在动脉粥样硬化发生发展中的研究进展

炎症小体(inflammasome)是免疫细胞内由多种蛋白质所组成的复合体,属于胞浆型模式识别受体(pattern recognition receptor,PRR)。它作为固有免疫系统的重要组分在机体免疫反应和疾病发生过程中具有重要作用。近年来的研究表明炎症小体是炎症免疫反应的核心。由于能被多种类型的病原体或危险信号所激活,NLRP3(NOD样受体蛋白-3)炎症小体在多种疾病过程中,包括动脉粥样硬化症、家族性周期性自身炎症反应、阿尔海默茨病和2型糖尿病等都发挥了关键作用。因此,NLRP3(NOD样受体蛋白-3)炎症小体可能为各种炎症性疾病,包括动脉粥样硬化的治疗提供新的靶点。本文将对炎症小体在动脉粥样硬化发生发展中发挥的作用进行综述。     

Pathogen recognition and innate immunity

Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.