Inflammasome-Dependent Coagulation Activation in Sepsis

Wu, Runliu; Wang, Nian; Comish, Paul B.; Tang, Daolin; Kang, Rui

doi:10.3389/fimmu.2021.641750

Cited by 52 publications

(47 citation statements)

References 69 publications

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“…Innate immunity acts as the front line of defense against pathogen invasion and tissue damage. Inflammasomes serve as intracellular pattern recognition receptors to activate inflammatory caspases ( 5 ). In response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), canonical inflammasomes are activated as a multimolecular protein complex and platform to recruit caspase-1, leading to its autoproteolytic activation, subsequent production of mature interleukin (IL)-1β and IL-18, and a lytic form of cell death called pyroptosis.…”

Section: Introductionmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

2021

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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Section: Introductionmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

2021

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“…In patients with severe COVID-19, genetic variants studied here may be involved in more severe inflammatory conditions perhaps through STING signaling-mediated altered type I IFN production [31]. Indeed, very recently, inflammasome-dependent coagulation activation has been found to associate with excessive activation of the STING pathway [67], while beclin-1, a marker of autophagy, has been found to be increased in COVID-19 patients, particularly in severe patients, and its levels have been demonstrated to correlate with D-dimer levels [71].…”

Section: Discussionmentioning

confidence: 88%

“…This is a limit of our study. Coagulation biomarkers, including D-dimers, are frequently altered during severe inflammation [67][68][69][70]. In patients with severe COVID-19, genetic variants studied here may be involved in more severe inflammatory conditions perhaps through STING signaling-mediated altered type I IFN production [31].…”

Section: Discussionmentioning

confidence: 89%

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

Zanella

Zacchi

Piva

et al. 2021

IJMS

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A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

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“…The inflammasome is defined as a cytosolic multiprotein signaling complex that controls the response to diverse pathogen microorganisms [59][60][61].…”

Section: Inflammasomementioning

confidence: 99%

“…STING1 mRNA expression in blood mononuclear cells is correlated with the severity of disseminated intravascular coagulation in patients with sepsis. STING1 mediator type1 interferon response is of restricted influence for inflammasome-mediated coagulation [61].…”

Section: Inflammasomementioning

confidence: 99%

Endothelial Cell Participation in Inflammatory Reaction

Wautier

2021

IJMS

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Inflammation is an old concept that has started to be considered as an important factor in infection and chronic diseases. The role of leukocytes, the plasmatic components, then of the mediators such as prostaglandins, cytokines, and, in recent decades, of the endothelium has completed the concept of the inflammation process. The function of the endothelium appeared to be crucial as a regulator or the initiator of the inflammatory process. Culture of human endothelial cells and experimental systems made it possible to define the molecular basis of inflammation in vascular diseases, in diabetes mellitus, atherosclerosis, vasculitis and thromboembolic complications. Advanced glycation end product receptor (RAGE), present on endothelial cells (ECs) and monocytes, participates in the activation of these cells in inflammatory conditions. Inflammasome is a cytosolic multiprotein that controls the response to diverse microorganisms. It is positively regulated by stimulator of interferon response CGAMP interactor-1 (STING1). Angiogenesis and thrombotic events are dysregulated during inflammation. ECs appear to be a protector, but also a possible initiator of thrombosis.

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Inflammasome-Dependent Coagulation Activation in Sepsis

Cited by 52 publications

References 69 publications

Inflammasomes in Alveolar Bone Loss

Inflammasomes in Alveolar Bone Loss

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

Endothelial Cell Participation in Inflammatory Reaction

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