Roles of Toll-like receptors in innate immune responses

Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses.     

Toll样受体在先天性免疫反应中的作用

先天性免疫识别侵袭的微生物,引起宿主防御反应.然而,先天性免疫识别的分子机制还不清楚.最近,有人发现了Toll样受体家族(TLRs),并阐明了这些受体在微生物识别中的主要作用.TLR基因家族包括11个成员,也可能更多.每种引起TLR先天性免疫反应的微生物类型各不相同.先天性免疫的激活引起特定抗原获得性免疫的发展.因此,TLRs控制先天性免疫反应和获得性免疫反应.     

Mast cells in allergic asthma and beyond

Mast cells have been regarded for a long time as effector cells in IgE mediated type I reactions and in host defence against parasites. However, they are resident in all environmental exposed tissues and express a wide variety of receptors, suggesting that these cells can also function as sentinels in innate immune responses. Indeed, studies have demonstrated an important role of mast cells during the induction of life-saving antibacterial responses. Furthermore, recent findings have shown that mast cells promote and modulate the development of adaptive immune responses, making them an important hinge of innate and acquired immunity. In addition, mast cells and several mast cell-produced mediators have been shown to be important during the development of allergic airway diseases. In the present review, we will summarize findings on the role of mast cells during the development of adaptive immune responses and highlight their function, especially during the development of allergic asthma.     

Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging

Innate and adaptive immunity are the major defence mechanisms of higher organisms against inherent and environmental threats. Innate immunity is present already in unicellular organisms but evolution has added novel adaptive immune mechanisms to the defence armament. Interestingly, during aging, adaptive immunity significantly declines, a phenomenon called immunosenescence, whereas innate immunity seems to be activated which induces a characteristic pro-inflammatory profile. This process is called inflamm-aging. The recognition and signaling mechanisms involved in innate immunity have been conserved during evolution. The master regulator of the innate immunity is the NF-kB system, an ancient signaling pathway found in both insects and vertebrates. The NF-kB system is in the nodal point linking together the pathogenic assault signals and cellular danger signals and then organizing the cellular resistance. Recent studies have revealed that SIRT1 (Sir2 homolog) and FoxO (DAF-16), the key regulators of aging in budding yeast and Caenorhabditis elegans models, regulate the efficiency of NF-kB signaling and the level of inflammatory responses. We will review the role of innate immunity signaling in the aging process and examine the function of NF-kB system in the organization of defence mechanisms and in addition, its interactions with the protein products of several gerontogenes. Our conclusion is that NF-kB signaling seems to be the culprit of inflamm-aging, since this signaling system integrates the intracellular regulation of immune responses in both aging and age-related diseases.     

Innate signaling and regulation of Dendritic cell immunity

Dendritic cells are crucial in pathogen recognition and induction of specific immune responses to eliminate pathogens from the infected host. Host recognition of invading microorganisms relies on evolutionarily conserved, germline-encoded pattern-recognition receptors (PRRs) that are expressed by DCs. The best-characterized PRR family comprises the Toll-like receptors (TLRs) that recognize bacteria or viruses. In addition to TLRs, intracellular Nod-like receptors and the membrane-associated C-type lectins (CLRs) function as PRRs. Many of these innate receptors also have an important function in natural host homeostatic responses, such as the maintenance of gut homeostasis. Clearly, more indications are hinting at a fine-tuning of immune responses by a concerted action of these PRRs on the recognition of pathogen components and the consequent signalling events that are created. It is becoming increasingly clear that these PRRs can initiate specific signalling events that modulate the production of inflammatory cytokines, phagocytosis, intracellular routing of antigen, release of oxidative species and DC maturation and the subsequent development of adaptive immunity. Notably, members within one family of PRRs can trigger opposite signalling features, indicating that the ultimate outcome of pathogen-induced immune responses depends on the pathogen signature and the collective PRRs involved.     

Anticipating innate immunity without a Toll

Earthworm innate immunity depends upon small and large leukocytes (coelomocytes) that synthesize and secrete humoral antimicrobial molecules (e.g. lysenin, fetidin, eiseniapore, coelomic cytolytic factor [CCF]; Lumbricin I). Small coelomocytes (cytotoxic) are positive (CD11a, CD45RA, CD45RO, CDw49b, CD54, beta(2)-m and Thy-1 [CD90]; CD24; TNF-alpha) but negative using other mammalian markers. Large coelomocytes (phagocytic) are uniformly negative. Specific earthworm anti-EFCC 1, 2, 3, 4 mAbs are negative for Drosophila melanogaster hemocytes and mammalian cells but positive those of earthworms. Coelomocytes contain several lysosomal enzymes involved in phagocytosis and a pattern recognition molecule (CCF) that may trigger the prophenoloxidase cascade a crucial innate immune response. Earthworms and other invertebrates possess natural, non-specific, non-clonal, and non-anticipatory immune response governed by germ line genes. Toll and Toll-like receptor signaling is essential for phagocytosis and antimicrobial peptide synthesis and secretion in insects and vertebrates but has not yet been shown to be essential in earthworm innate responses.     

Toll-like receptors and the eye

PURPOSE OF REVIEW: This review will describe the structure, expression/distribution and functional activity of Toll-like receptors, in particular in the ocular structures. It will also discuss innate and adaptive immune responses, by exploring the possible modulation/regulation of innate and adaptive immunity by Toll-like receptors, in view of recent findings observed in the ocular surface. RECENT FINDINGS: Current knowledge indicates that Toll-like receptors represent essential elements in host defence against pathogens, a prerequisite to the induction of adaptive immune responses. The expression/distribution of Toll-like receptors in the healthy eye highlights the possible function of Toll-like receptors in both innate and adaptive responses during pathological conditions of the ocular surface. SUMMARY: Recent findings have greatly increased the knowledge of the possible role of Toll-like receptors in innate and adaptive immune responses. Toll-like receptors seem to play different roles in a wide range of activities of the immune system, and might represent an exclusive link between innate and adaptive responses under pathological conditions. Recent studies in ophthalmology have highlighted the role of Toll-like receptors in infections (keratitis) as well as in allergic states of the ocular surface. This review thus describes the relationship between Toll-like receptors and the main immune/structural cells taking part in inflammatory disorders. Understanding the complex mechanisms underlying Toll-like receptor localization and function will provide additional data that might help devise novel therapeutic approaches involving Toll-like receptors and their agonists, in an attempt to modulate the biased immune system.     

Regulators of the Toll and Imd pathways in the Drosophila innate immune response

The innate immune response is the first line of defense against microbial infections in both insects and mammals. Systematic analysis of the innate immune response in the model organism Drosophila melanogaster has provided important insights into the mechanisms of pathogen recognition and host response. Recognition of pathogen-associated molecules, such as peptidoglycans, stimulates the Toll and immune deficiency (Imd) pathways to induce antimicrobial responses. The Toll and Imd pathways are homologous to the mammalian Toll-like receptor (TLR) and tumor necrosis factor receptor (TNFR) signaling pathways, respectively, and are essential for Drosophila to survive infection. In this Review, we will discuss the recent genetic, genomic and RNA interference analyses that have unveiled additional intricacy in the Toll and Imd pathways.     

Contribution of innate immune responses towards resistance to African trypanosome infections

During the course of African trypanosomiasis, an intact monocytic cell system appears to be crucial for the initiation and maintenance of antitrypanosome responses and could be critical for the survival of trypanosome-infected host. Monocytic cells in turn require support from other components of the innate immunity as well as adaptive immunity for effective and sustained control of trypanosome infections. In this review, the contribution of specific components of the innate immune system towards resistance to African trypanosomes is discussed in the context of host survival and the ideas presented are expected to stimulate more debate and research on host innate mechanisms of defence against African trypanosomiasis.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展.特别是在关于模式识别受体的发现和功能研究方面.模式识别受体能识别病原相关的分子模式.先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活.如果没有先天免疫,后天获得性免疫的功能会变得很微弱.Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展.特别是在关于模式识别受体的发现和功能研究方面.模式识别受体能识别病原相关的分子模式.先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活.如果没有先天免疫,后天获得性免疫的功能会变得很微弱.Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗.     

Innate immunity: from lymphocyte mitogens to Toll-like receptors and back

Innate immunity, our inborn immediate defence mechanism, was thought for a long time to be non-specific and, consequently, research into innate mechanisms often took second place to research into adaptive immunity. In recent decades, however, the spotlight has shone on groundbreaking advances into mechanisms of innate immunity; from the hypothesis that mitogen receptors distinguish between 'self' and 'very-different-from-self' in the mid-1970s to the refining of the concept by Janeway in 1989, the identification of Toll-like molecules as mitogen receptors, and finally the cloning of the first mammalian Toll-like receptor (TLR) in 1997. We now know that innate immune activation has a role in the control of adaptive immune responses, and many more TLRs and their ligands have been characterised.     

脾酪氨酸激酶在抗真菌免疫反应中的作用

真菌感染是免疫功能缺陷或免疫功能低下患者生命健康的一大威胁.机体通过固有免疫和适应性免疫反应发挥抗真菌作用.脾酪氨酸激酶(Syk)为一种非受体型酪氨酸激酶,Syk可以影响T细胞、B细胞和树突状细胞(DC)的活化以及巨噬细胞和中性粒细胞介导的吞噬作用,现研究证实Syk在抗真菌免疫反应中同样起着重要作用.多种模式识别受体(PRRs)包括C型凝集素受体(CLRs)、Toll样受体( TLRs)、补体受体3(CR3)等可以识别真菌并启动抗真菌免疫反应.Syk可通过直接或间接方式与多种PRRs耦联,并在抗真菌免疫反应中发挥不同作用.     

The Evolutionary Role of the IL-33/ST2 System in Host Immune Defence

Interleukin (IL)-33 is a recently identified pleiotropic cytokine, which can orchestrate complex innate and adaptive immune responses in immunity and disease. It has been characterized as a cytokine of the IL-1 family and affects a wide range of immune cells by signalling through its receptor ST2L. Accumulating evidence suggests a crucial role of IL-33/ST2 in inducing and modifying host immune responses against a variety of pathogens including parasites, bacteria, viruses and fungi as well as sterile insults of both endogenous and exogenous source. In this review, we endeavour to give a comprehensive overview of the current knowledge about the role of IL-33 and its receptor ST2 in host defence against infections.     

Complement: coming full circle

The complement system has long been known to be a major element of innate immunity. Traditionally, it was regarded as the first line of defense against invading pathogens, leading to opsonization and phagocytosis or the direct lysis of microbes. However, from the second half of the twentieth century on, it became clear that complement is also intimately involved in the induction and “fine tuning” of adaptive B- and T-cell responses as well as lineage commitment. This growing recognition of the complement system’s multifunctional role in immunity is consistent with the recent paradigm that complement is also necessary for the successful contraction of an adaptive immune response. This review aims at giving a condensed overview of complement’s rise from a simple innate stop-and-go system to an essential and efficient participant in general immune homeostasis and acquired immunity.     

Control of antiviral immunity by pattern recognition and the microbiome

Human skin and mucosal surfaces are in constant contact with resident and invasive microbes. Recognition of microbial products by receptors of the innate immune system triggers rapid innate defense and transduces signals necessary for initiating and maintaining the adaptive immune responses. Microbial sensing by innate pattern-recognition receptors is not restricted to pathogens. Rather, proper development, function, and maintenance of innate and adaptive immunity rely on continuous recognition of products derived from the microorganisms indigenous to the internal and external surfaces of mammalian host. Tonic immune activation by the resident microbiota governs host susceptibility to intestinal and extra-intestinal infections, including those caused by viruses. This review highlights recent developments in innate viral recognition leading to adaptive immunity, and discusses potential links between viruses, microbiota, and the host immune system. Furthermore, we discuss the possible roles of microbiome in chronic viral infection and pathogenesis of autoimmune disease and speculate on the benefit for probiotic therapies against such diseases.     

Phagocytosis mediates specificity in the immune defence of an invertebrate, the woodlouse Porcellio scaber (Crustacea: Isopoda)

Specificity and memory are the hallmarks of the adaptive immune system of vertebrates. However, phenomena of specificity upon priming of immunity have recently been demonstrated also in invertebrates, which rely exclusively on innate immune defence. It has been suggested that phagocytosis might represent a core candidate for such specificity in invertebrates. We here developed in vitro phagocytosis measurements for different bacteria in the woodlouse Porcellio scaber (Crustacea: Isopoda). After immune priming with heat-killed bacteria, hemocytes showed increased phagocytosis of a previously encountered bacterial strain compared to other bacteria. These data support the role of phagocytosis in invertebrate immunological specificity and suggest a high degree of specificity that even enables to differentiate between strains of the same bacterial species.