Inflammasomes are multiprotein enzymatic complexes that form in the cytosol in response to infections or cell injury, and produce proteolytically active caspase-1 that generates bio logically active forms of the inflammatory cytokines IL-1β and IL-18 (Fig. 1). IL-1β and IL-18 are two homologous cytokines that are produced as inactive precursors and must be proteolytically cleaved by the enzyme caspase-1 to become active cytokines that are released from the cell and promote inflammatory responses. Most inflammasomes (so-called canonical inflammasomes) are composed of oligomers of a sensor, caspase-1, and an adaptor that links the two, and these oligomeric complexes form only when the sensors detect changes in the cell indicating the presence of infection or damage. Thus, inflammation mediated by IL-1β and IL-18 occurs when there are PAMPs or DAMPs in the cytosol, indicating infection or cell injury.

Fig1. Inflammasomes. Activation of three different canonical inflammasomes using NLRP3, NLRC4, or AIM2 as sensors, and the noncanonical inflammasomes composed of caspases 4, 5, or 11 are shown. Some of the ligands or cellular conditions that induce the assembly each of these inflammasomes are indicated. The canonical inflammasomes assemble as multimeric complexes including the NOD-like receptor (NLR) sensors, adaptor proteins such as ASC or NAIP5, and procaspase 1, leading to proteolytic generation of active caspase 1, which processes pro-interleukin (IL)-1β and pro-IL-18 to active IL-1β and IL-18. Inflammasome-activated caspase-1 can also proteolytically cleave the cytosolic protein gasdermin D, generating an N-terminal fragment that polymerizes in the plasma membrane, forming a pore that lets IL-1β out of and water and ions into the cell, leading to cell death by osmotic lysis. This pathway of cell death is called pyroptosis, because it is accompanied by inflammation and fever due to IL-1 released from the dying cells. Cytoplasmic lipopolysaccharide (LPS) induces the assembly of procaspase-4, -5, or -11 molecules to form nonconical inflammasomes that are multimers of active caspase 4, 5, or 11, which can also cleave gasdermin D, leading to gasdermin-N pore formation and pyroptosis. AIM2, Absent in melanoma-2; ASC, apoptosis-associated speck-like protein containing a CARD; ATP, adenosine triphosphate; DAMPs, damage-associated molecular patterns; dsDNA, double-stranded DNA; NOD, nucleotide oligomerization domain; PAMPs, pathogen-associated molecular pat terns; ROS, reactive oxygen species; TLR, Toll-like receptor.

Inflammasomes can form with several different sensor proteins. NLR family sensors found in different inflammasomes include NLRB, NLRC4, and at least six NLRP proteins (see Table 1). Sensors that are not in the NLR family but are used by other inflammasomes include members of the AIM2 family, including AIM2 and IFI16, which we discuss later as DNA sensors. These proteins contain a DNA-sensing domain and a pyrin domain. Pyrin is another non-NLR sensor protein that contains an N-terminal pyrin domain and participates in the formation of an inflammasome. The gene encoding pyrin is mutated in familial Mediterranean fever, as discussed later.

Table1. NOD-Like Receptors

T he formation of the inflammasome is induced either when sensor proteins in the cytosol directly recognize microbial prod ucts or when sensors detect changes in the amount of endogenous molecules or ions in the cytosol that indirectly indicate the presence of infection or cell damage. In response to the PAMPs or indirect signals, the sensors become able to bind other proteins through homotypic interactions between shared structural domains, thereby forming the inflammasome complex. For example, after binding of a ligand, multiple identical NLRP3 proteins interact to form an oligomer, and each NLRP3 protein in the oligomer binds an adaptor protein called ASC (apoptosis associated speck-like protein containing a CARD). The binding of ASC to sensors such as NLRP proteins causes ASC to undergo a conformational alteration that triggers similar con formational changes of other ASC molecules in the cytosol by a self-propagating mechanism. This results in the formation of filaments of ASC that can cluster and recruit an inactive pre cursor of caspase-1 called procaspase-1. The recruitment and consequent clustering of procaspase-1 result in the proteolytic generation of active caspase-1. Caspases are proteases with cysteine residues in their active site that cleave substrate proteins at aspartate residues. Although several other caspases participate in a form of cell death called apoptosis, the main function of caspase-1 is to cleave the inactive cytoplasmic precursor forms of IL-1β and IL-18. Caspase-1 cleavage generates active forms of these cytokines, which then leave the cell and perform various proinflammatory functions. IL-1β lacks a signal peptide required for the secretion of most proteins from cells; thus, another mechanism is required for its release from the cytosol. That mechanism involves caspase-1 cleavage of a cytosolic protein called gasdermin D, removing the inhibitory C-terminal domain and generating an N-terminal fragment that polymerizes to form pores in the plasma membrane through which processed IL-1β may leave the cell. In some cell types, the gasdermin pores also contribute to a form of cell death called pyroptosis, described later. We will describe the action of IL-1β and IL-18 in the inflammatory response in detail later in this chapter. Suffice it to say here that the inflammation induced by IL-1 serves a protective function by recruiting phagocytes that eliminate the microbes and damaged cells that incited the formation of the inflammasome.

Inflammasome activation is induced by a wide variety of cytoplasmic stimuli that are often associated with infections and cell stress, including microbial products, environmentally or endogenously derived substances that tend to form crystals, and reduction in cytosolic potassium ion (K+) concentrations (see Fig. 1). NLRC4 recognizes cytosolic flagellin and components of the type III secretion system of bacteria. NLRP1 recognizes the anthrax lethal toxin. NLRP3 senses many DAMPs and PAMPs, including uric acid crystals, aluminum hydroxide crystals used in vaccine adjuvants, cholesterol crystals, adenosine triphosphate (ATP) released from mitochondria, silica, bacterial products, bacterial toxins produced by streptococci and staphylococci, bacterial DNA-RNA hybrids, and the influenza virus. Pyrin responds to numerous bacterial toxins that all mediate post-translational modification of endogenous Rho family GTPases.

The mechanism by which such varied molecules activate the same NLR sensors is unclear. The structural diversity of the agents that activate these sensors suggests that they do not all directly bind to NLR proteins but may act by inducing a shared set of changes in endogenous cytoplasmic conditions that activate the NLRs. Reduced cytoplasmic potassium ion concentration may be one such common mechanism because reductions in cellular K+ induced by some bacterial pore-forming toxins can activate inflammasomes, and many of the other known inflammasome activators, such as extracellular ATP, cause increased K+ efflux from cells. Another common mechanism implicated in inflammasome activation is the generation of reactive oxy gen species (ROS), which are toxic free radicals of oxygen that are often produced during cell injury. Inflammasome-activating crystals may work by damaging lysosomal membranes, thereby releasing ROS into the cytosol, where they are detected by the sensors that stimulate inflammasome formation.

Inflammasome activation of caspases also causes an inflammatory form of programmed cell death of macrophages and DCs (but not of neutrophils and most other cell types) called pyroptosis (see Fig. 1). This form of cell death is the result of plasma membrane pores formed by caspase-generated fragments of gasdermin D, mentioned earlier as a pathway for IL-1β release from cells. These pores contribute to osmotic death of macrophages and DCs, characterized by the influx of fluid, swelling of cells, loss of plasma membrane integrity, and release of inflammatory mediators, including IL-1β, IL-18, TNF, IL-6, and IL-8. Cells undergoing pyroptosis may release abundant IL-1 in part because gasdermin pores enhance K+ efflux, which activates the NLRP3 inflammasome. Pyroptosis also results in the death of certain microbes that gain access to the cytosol. Pyroptosis is induced by canonical inflammasomes using the sensors NLRC4, NLRP1, AIM2, pyrin, and NLRP3, all leading to activation of caspase-1, which cleaves gasdermin D. Pyroptosis may also be induced by the activation of a noncanonical inflammasome pathway that uses a different caspase (caspase-11 in rodents; caspase-4 or caspase-5 in humans). Bacterial LPS in the cytosol can directly bind to caspase-11, which leads to proteolytic activation of gasdermin D with pore formation causing pyroptosis and also indirectly leads to NLRP3 inflammasome activation and generation of active IL-1β. The amplification of inflammation provided by pyroptosis enhances bacterial clearance but may also contribute to septic shock, a severe systemic reaction to inflammatory cytokines. The absence of caspase-11 in genetically engineered mice protects them from LPS-induced septic shock.

The discovery that some crystalline substances are potent inflammasome activators has changed our understanding of certain inflammatory diseases. Gout is a painful inflammatory condition of the joints that has long been known to be associated with deposition of monosodium urate crystals in joints. Experimental evidence suggests that when these crystals are phagocytosed, they damage the lysosomal membranes of the cells, and this leads to activation of inflammasomes and subsequent inflammation. Based on these findings, IL-1 antagonists have been used to effectively treat cases of severe gout that are resistant to conventional anti-inflammatory drugs. Similarly, pseudogout is caused by deposition of calcium pyrophosphate crystals and inflammasome activation. Occupational inhalation of silica and asbestos can cause chronic inflammatory and fibrotic disease of the lung, and there is also interest in the potential utility of blocking the inflammasome or IL-1 to treat these diseases.

Dysregulated activation of inflammasomes, due to autosomal gain-of-function mutations in one or another of their component proteins or loss-of-function mutations in their regulators, leads to inappropriately triggered and excess IL-1 production. The result is recurrent attacks of fever and localized inflammation, most commonly in the skin, joints, and abdominal cavity. These disorders are called IL-1β–activation syndromes or inflammasomopathies, and are part of a larger group of genetic disorders called autoinflammatory syndromes, generally characterized by spontaneous cytokine-driven inflammation without an overt inciting trigger (Table2). Most of these disorders are caused by inherited germline mutations of single genes encoding regulators of inflammatory responses, but there are many examples of similar disorders due to somatic mutations of the same genes, often restricted to myeloid lineages. Autoinflammatory diseases are distinct from autoimmune diseases, which are disorders of adaptive immunity caused by antibodies and/or T cells reactive with self antigens. However, some autoinflammatory dis eases are associated with autoimmune diseases, such as systemic lupus erythematous. This probably reflects the fact that innate immune responses are needed in addition to antigens to initiate T- and B-cell responses, and thus dysregulated production of innate cytokines that occurs in autoinflammatory syndromes may contribute to inappropriate activation of self-reactive lymphocytes and subsequent autoimmune disease.

Table2. Selected Monogenic Autoinflammatory Syndromes

The longest studied of the inflammasome-related auto inflammatory syndromes is familial Mediterranean fever, caused by mutation of the MEFV gene, which encodes pyrin. Autoinflammatory diseases caused by mutations in NLRP3 (also known as cryopyrin) are called cryopyrin-associated peri odic syndromes (CAPS). Patients with CAPS can be successfully treated with IL-1 antagonists, as predicted from our understanding of the consequences of inflammasome activation.

A great deal of interest in inflammasomes has recently been generated by findings that they may be activated by excessive amounts of endogenous substances deposited in tissues in the setting of various diseases. These substances include cholesterol crystals within macrophages in atherosclerosis, free fatty acids and lipids in adipose tissue in obesity-associated metabolic syn drome and type 2 diabetes, and β-amyloid in Alzheimer disease. In all these situations, activation of inflammasomes leads to pro duction of IL-1 and inflammation, which may contribute to the pathogenesis of the diseases. Such findings have spurred clinical trials to alleviate some of these diseases using IL-1 antagonists.

اخر الاخبار

اخبار العتبة العباسية المقدسة

شعبة التوجيه الديني النسوي تنظم مسابقة ثقافية بذكرى ولادة السيدة المعصومة (عليها السلام)

المجمع العلمي ينظّم محاضرةً تربوية لطلبة مشروع حفظ القرآن الكريم في كربلاء

قسم الشؤون الفكرية يقيم معرضًا وثائقيًا ضمن مهرجان (الشهيد) في جامعة الكوفة

قسم الشؤون الدينية يشهد إقبالًا واسعًا من المؤمنين لتنظيم عقود الزواج

المزيد

الآخبار الصحية

دواء جديد يحمي القلب ويعزز علاج السرطان في آن واحد

سر غذائي بسيط لحماية القلب مع التقدم في العمر

علامات تشير إلى اختلال عمل الغدة الدرقية

السمنة واللقاحات.. دراسة تكشف تأثيراً سلبياً

المزيد

الآخبار التكنلوجية

البعوض في آيسلندا إشارة مبكرة على تحولات بيئية في القطب الشمالي

صاروخ يطلق قمرا اصطناعيا في مدار خاطئ

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المزيد

مواضيع ذات صلة

Antigen Capture and the Functions of Antigen-Presenting Cells

Cytosolic DNA Sensors and the STING Pathway

RIG-Like Receptors

Antigens

NOD-Like Receptors: NOD1 and NOD2

Recognition of Microbes and Damaged Tissue by the Innate Immune System

Overview of Innate Immunity

Transplantation of Tissues and Organs

Rh Blood Types

O-A-B Blood Types

Allergy and Hypersensitivity

The Antiviral Response