Alarmins, inflammasomes and immunity

Saïd-Sadier, Najwane; Ojcius, David M.

doi:10.4103/2319-4170.104408

Cited by 125 publications

(95 citation statements)

References 136 publications

(170 reference statements)

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“…During injury or damage-induced responses a number of endogenous molecules, including DNA, reactive oxygen species (ROS), laminins or S100 proteins, act as damage-associated molecular patterns (DAMPs) or alarmins that bind TLRs, integrins and other receptors to stimulate the immune system, activate dendritic cells and recruit neutrophils 16 . The role of DAMPs in the response to injury and the initiation of inflammation in Crohn’s disease is increasingly recognized and investigated 17 .…”

Section: Injury Inflammation and Fibrosismentioning

confidence: 99%

Mechanisms That Mediate the Development of Fibrosis in Patients With Crohnʼs Disease

Li¹,

Kuemmerle

2014

Inflammatory Bowel Diseases

104

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Crohn’s disease is complicated by the development of fibrosis and stricture in ~30–50% of patients over time. The pathogenesis of fibrostenotic disease is multifactorial involving the activation of mesenchymal cells by cytokines, growth factors and other mediators released by immune cells, epithelial cells and mesenchymal cells themselves. Transforming growth factor-β (TGF-β), a key activator of mesenchymal cells, is central to the process of fibrosis and regulates numerous genes involved in the disordered wound healing including collagens, and other extracellular matrix proteins, connective tissue growth factor (CTGF), and insulin-like growth factors (IGFs). The activated mesenchymal compartment is expanded by recruitment of new mesenchymal cells via epithelial to mesenchymal transition, endothelial to mesenchymal transition and invasion of circulating fibrocytes. Cellular hyperplasia and increased extracellular matrix (ECM) production, particularly collagens, from fibroblasts, myofibroblasts and smooth muscle cells add to the disturbed architecture and scarring on the intestine. ECM homeostasis is further disrupted by alterations in the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) in the gut. Among the 163 susceptibility genes identified that contribute to susceptibility in IBD mutations in NOD2/CARD15, innate immune system components, and autophagy jointly contribute to the activation of mesenchymal cells and pathogenesis of fibrosis in this polygenic disorder. Numerous growth factorscytokinesand other mediators. The review focuses on the molecular mechanism that regulate mesenchymal cell function, particularly smooth muscle cells, the largest compartment of mesenchyme in the intestine, that lead to fibrosis in Crohn’s disease.

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Section: Injury Inflammation and Fibrosismentioning

confidence: 99%

Mechanisms That Mediate the Development of Fibrosis in Patients With Crohnʼs Disease

Li¹,

Kuemmerle

2014

Inflammatory Bowel Diseases

104

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“…Recognition of pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) is generally described as a first step that leads to synthesis of pro-IL-1β but is not sufficient for secretion. The infected cell must be stimulated with a second signal which can be released from infected cells or other stressed cells, called damage-associated molecular patterns (DAMPs) [1]. Pro-IL-1β is then proteolytically cleaved into the 17 kDa biologically active form [2] and can be released into the extracellular space through a variety of secretory mechanisms present in monocytes and macrophages [1,3–5].…”

Section: Introductionmentioning

confidence: 99%

<b><i>Porphyromonas gingivalis</i></b> Fimbriae Dampen P2X7-Dependent Interleukin-1β Secretion

et al. 2014

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Porphyromonas gingivalis is a major contributor to the pathogenesis of periodontitis, an infection-driven inflammatory disease that leads to bone destruction. This pathogen stimulates pro-interleukin (IL)-1β synthesis but not mature IL-1β secretion, unless the P2X7 receptor is activated by extracellular ATP (eATP). Here, we investigated the role of P. gingivalis fimbriae in eATP-induced IL-1β release. Bone marrow-derived macrophages (BMDMs) from wild-type (WT) or P2X7-deficient mice were infected with P. gingivalis (381) or isogenic fimbria-deficient (DPG3) strain with or without subsequent eATP stimulation. DPG3 induced higher IL-1β secretion after eATP stimulation compared to 381 in WT BMDMs, but not in P2X7-deficient cells. This mechanism was dependent on K⁺ efflux and Ca²⁺-independent phospholipase A₂ activity. Accordingly, non-fimbriated P. gingivalis failed to inhibit apoptosis via the eATP/P2X7 pathway. Furthermore, P. gingivalis-driven stimulation of IL-1β was Toll-like receptor 2 and MyD88 dependent, and not associated with fimbria expression. Fimbria-dependent down-modulation of IL-1β was selective, as levels of other cytokines remained unaffected by P2X7 deficiency. Confocal microscopy demonstrated the presence of discrete P2X7 expression in the absence of P. gingivalis stimulation, which was enhanced by 381-stimulated cells. Notably, DPG3-infected macrophages revealed a distinct pattern of P2X7 receptor expression with a marked focus formation. Collectively, these data demonstrate that eATP-induced IL-1β secretion is impaired by P. gingivalis fimbriae in a P2X7-dependent manner.

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“…First, pro-IL-1␤ is transcribed via NF-B activation following signaling from pattern recognition receptors (PRRs), such as Tolllike receptors (TLRs) (signal 1). TLR signaling is initiated by binding to ligands, known as pathogen-associated molecular patterns (PAMPs), such as LPS, flagella, or lipoprotein (18), and then pro-IL-1␤ is cleaved by the activated inflammasome, which consists of caspase-1, nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), and an adapter molecule, ASC, which is the designation for apoptosis-associated speck-like protein containing a carboxy-terminal caspase recruitment domain (CARD) (signal 2). NLRs recognize PAMPs as well as danger-associated molecular patterns (DAMPs), including nuclear DNA or RNA, and cytosolic proteins (18).…”

mentioning

confidence: 99%

“…TLR signaling is initiated by binding to ligands, known as pathogen-associated molecular patterns (PAMPs), such as LPS, flagella, or lipoprotein (18), and then pro-IL-1␤ is cleaved by the activated inflammasome, which consists of caspase-1, nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), and an adapter molecule, ASC, which is the designation for apoptosis-associated speck-like protein containing a carboxy-terminal caspase recruitment domain (CARD) (signal 2). NLRs recognize PAMPs as well as danger-associated molecular patterns (DAMPs), including nuclear DNA or RNA, and cytosolic proteins (18). Interestingly, while IL-1␤ secretion from C. pneumoniae-infected cells requires both NF-B activation via TLR2/4 recognition (signal 1) and NLRP3 inflammasome activa-tion (signal 2) (5,19,20), LPS-primed macrophages stimulated with carbon nanoparticles activate the NLRP3 inflammasome (signal 2) (12)(13)(14).…”

mentioning

confidence: 99%

Synergistic Costimulatory Effect of Chlamydia pneumoniae with Carbon Nanoparticles on NLRP3 Inflammasome-Mediated Interleukin-1β Secretion in Macrophages

et al. 2015

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The obligate intracellular bacterium Chlamydia pneumoniae is not only a causative agent of community-acquired pneumonia but is also associated with a more serious chronic disease, asthma, which might be exacerbated by air pollution containing carbon nanoparticles. Although a detailed mechanism of exacerbation remains unknown, the proinflammatory cytokine interleukin-1␤ (IL-1␤) is a critical player in the pathogenesis of asthma. C. pneumoniae induces IL-1␤ in macrophages via NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activation and Toll-like receptor 2/4 (TLR2/4) stimulation. Carbon nanoparticles, such as carbon nanotubes (CNTs), can also evoke the NLRP3 inflammasome to trigger IL-1␤ secretion from lipopolysaccharide-primed macrophages. This study assessed whether costimulation of C. pneumoniae with CNTs synergistically enhanced IL-1␤ secretion from macrophages, and determined the molecular mechanism involved. Enhanced IL-1␤ secretion from C. pneumoniae-infected macrophages by CNTs was dose and time dependent. Transmission electron microscopy revealed that C. pneumoniae and CNTs were engulfed concurrently by macrophages. Inhibitors of actin polymerization or caspase-1, a component of the inflammasome, significantly blocked IL-1␤ secretion. Gene silencing using small interfering RNA (siRNA) targeting the NLRP3 gene also abolished IL-1␤ secretion. Other inhibitors (K ؉ efflux inhibitor, cathepsin B inhibitor, and reactive oxygen species-generating inhibitor) also blocked IL-1␤ secretion. Taken together, these findings demonstrated that CNTs synergistically enhanced IL-1␤ secretion from C. pneumoniae-infected macrophages via the NLRP3 inflammasome and caspase-1 activation, providing novel insight into our understanding of how C. pneumoniae infection can exacerbate asthma. Chlamydia pneumoniae is an obligate intracellular bacterium and a causative agent of respiratory tract infections, including community-acquired pneumonia (1, 2). The seroprevalence rates of C. pneumoniae infection, which start to rise relatively early in childhood, are increased by 50% at 20 years of age and subsequently reach 70 to 80% by 60 to 70 years of age (3, 4), suggesting most individuals will have had some exposure to the bacterium in their lifetime. Therefore, C. pneumoniae is likely a ubiquitous pathogen in individuals worldwide (4). The symptoms of pulmonary infection vary considerably according to age from asymptomatic or mild illness to serious pneumonia, especially in pediatric infection (1-3). Regarding this, several studies indicate that bacterial infection might exacerbate pulmonary inflammation and thus is associated with a more serious chronic disease, asthma (3). The proinflammatory cytokine interleukin-1␤ (IL-1␤), which is induced by C. pneumoniae (5-8), is thought to play a critical role in the development of chronic inflammatory disease, although detailed mechanisms remain unclear. Air pollution containing carbon nanoparticles, environmental air contaminants that might be easily inhaled with C. pneu...

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Alarmins, inflammasomes and immunity

Cited by 125 publications

References 136 publications

Mechanisms That Mediate the Development of Fibrosis in Patients With Crohnʼs Disease

Mechanisms That Mediate the Development of Fibrosis in Patients With Crohnʼs Disease

<b><i>Porphyromonas gingivalis</i></b> Fimbriae Dampen P2X7-Dependent Interleukin-1β Secretion

Synergistic Costimulatory Effect of Chlamydia pneumoniae with Carbon Nanoparticles on NLRP3 Inflammasome-Mediated Interleukin-1β Secretion in Macrophages

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