Control of innate and adaptive immunity by the inflammasome

Ciraci, Ceren; Janczy, John R.; Sutterwala, Fayyaz S.; Cassel, Suzanne L.

doi:10.1016/j.micinf.2012.07.007

Cited by 66 publications

(56 citation statements)

References 65 publications

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“…This is particularly notable, as IL-1␤ levels were higher in coinfected mice than mice in the other infection groups at 48 hpi. IL-1␤ processing and secretion are mediated by caspase 1 activation via the NLRP3 inflammasome (45), which is potently induced by P. mirabilis (46) and can also be activated by uric acid crystals and other crystalline structures (47). NLRP3 may play a critical role in P. mirabilis pathogenesis, particularly the tissue damage that occurs during coinfection and possibly in dissemination to the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection

et al. 2017

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Urinary catheter use is prevalent in health care settings, and polymicrobial colonization by urease-positive organisms, such as Proteus mirabilis and Providencia stuartii, commonly occurs with long-term catheterization. We previously demonstrated that coinfection with P. mirabilis and P. stuartii increased overall urease activity in vitro and disease severity in a model of urinary tract infection (UTI). In this study, we expanded these findings to a murine model of catheter-associated UTI (CAUTI), delineated the contribution of enhanced urease activity to coinfection pathogenesis, and screened for enhanced urease activity with other common CAUTI pathogens. In the UTI model, mice coinfected with the two species exhibited higher urine pH values, urolithiasis, bacteremia, and more pronounced tissue damage and inflammation compared to the findings for mice infected with a single species, despite having a similar bacterial burden within the urinary tract. The presence of P. stuartii, regardless of urease production by this organism, was sufficient to enhance P. mirabilis urease activity and increase disease severity, and enhanced urease activity was the predominant factor driving tissue damage and the dissemination of both organisms to the bloodstream during coinfection. These findings were largely recapitulated in the CAUTI model. Other uropathogens also enhanced P. mirabilis urease activity in vitro, including recent clinical isolates of Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. We therefore conclude that the underlying mechanism of enhanced urease activity may represent a widespread target for limiting the detrimental consequences of polymicrobial catheter colonization, particularly by P. mirabilis and other urease-positive bacteria.KEYWORDS CAUTI, Enterococcus, Proteus mirabilis, Providencia stuartii, UTI, catheterassociated urinary tract infection, polymicrobial, urease, urinary tract infection U rinary catheters are common in health care settings and are utilized by over 60% of critically ill patients, 20% of patients in medical and surgical units, and 5 to 10% of residents in nursing homes (1-3). The incidence of bacteria in urine (bacteriuria) is 3 to 8% per day of catheterization, and long-term catheterization (Ͼ30 days) results in continuous bacteriuria (1). The microbial composition of urine colonization changes over time, initially involving Escherichia coli, Klebsiella pneumoniae, Serratia spp., Citrobacter spp., Enterobacter spp., Pseudomonas aeruginosa, and/or Gram-positive cocci and

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Section: Discussionmentioning

confidence: 99%

The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection

et al. 2017

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“…The significance of innate immunity lies not only in comprising the first line of defense against pathogenic and non-pathogenic insults, but also in developing an efficient adaptive immune response (20)(21)(22)(23)(24). The NLRP3 inflammasome provides multiprotein molecular platforms for the activation of caspase-1 and subsequent processing and the secretion of IL-1 family members, to engage innate immune defense (5,24).…”

Section: Discussionmentioning

confidence: 99%

“…The NLRP3 inflammasome provides multiprotein molecular platforms for the activation of caspase-1 and subsequent processing and the secretion of IL-1 family members, to engage innate immune defense (5,24). Given the importance of IL-1 family members associated with acute and chronic inflammation, understanding the role of the NLRP3 inflammasome in the initiation of innate immune response cannot be ignored (24). Therefore, we examined the effects of LPS/ATP on the expression of inflammatory cytokines and the components of the NLRP3 inflammasome in RAW264.7 macrophage cells.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide/adenosine triphosphate induces IL-1β and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells

Xie

Shen

Zhong

et al. 2014

International Journal of Molecular Medicine

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Abstract. The NOD-like receptor family, pyrin domaincontaining 3 (NLRP3) inflammasome plays pivotal roles in inflammation and autoimmunity. The NLRP3 inflammasome is activated in response to various signals, including pathogenassociated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). However, its role in inflammation remains unclear. In this study, we used lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to simulate an inflammatory environment as the testing model. We found that the exposure of RAW264.7 cells to LPS/ATP triggered the activation of caspase-1 (P<0.01) and the cleavage of interleukin (IL)-1β (P<0.01), as well as the release of other cytokines, such as IL-18 (P<0.01) and IL-33 (P<0.01). Extracellular potassium chloride at a high concentration (150 mM) abrogated the secretion of IL-1β and IL-18 (P<0.01), but did not reduce the processing of IL-33 (P>0.05). In addition, the silencing of NLRP3 with small interfering RNA (siRNA) suppressed the generation of proinflammatory cytokines, such as IL-1β (P<0.01), IL-18 (P<0.01), but not IL-33 (P>0.05), along with the decreased mRNA and protein expression of NLRP3 and caspase-1 (P<0.05). However, extracellular potassium at a high concentration and NLRP3 siRNA did not affect the level of apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC; P>0.05). Our results suggest that the NLRP3/ASC/caspase-1 axis participates in the regulation of pro-imflammatory cytokine secretion in RAW264.7 cells, particularly the generation of IL-1β and IL-18.

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“…In addition to vital NETosis, regions with Ly6G staining but lacking nuclear DAPI signal may be the result of P. mirabilis toxins directly attacking infiltrating immune cells (35,36). The potent immune response could be influenced by NLRP3-inflammasome activation; this pathway can be broadly activated by crystalline substances and specifically activated by P. mirabilis in the digestive tract (37,38). It is also possible that neutrophils directly contribute to cluster formation, such as by providing materials for aggregation (i.e., DNA).…”

Section: Dapimentioning

confidence: 99%

Proteus mirabilis fimbriae- and urease-dependent clusters assemble in an extracellular niche to initiate bladder stone formation

Schaffer

Norsworthy

Sun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The catheter-associated uropathogen Proteus mirabilis frequently causes urinary stones, but little has been known about the initial stages of bladder colonization and stone formation. We found that P. mirabilis rapidly invades the bladder urothelium, but generally fails to establish an intracellular niche. Instead, it forms extracellular clusters in the bladder lumen, which form foci of mineral deposition consistent with development of urinary stones. These clusters elicit a robust neutrophil response, and we present evidence of neutrophil extracellular trap generation during experimental urinary tract infection. We identified two virulence factors required for cluster development: urease, which is required for urolithiasis, and mannoseresistant Proteus-like fimbriae. The extracellular cluster formation by P. mirabilis stands in direct contrast to uropathogenic Escherichia coli, which readily formed intracellular bacterial communities but not luminal clusters or urinary stones. We propose that extracellular clusters are a key mechanism of P. mirabilis survival and virulence in the bladder.Proteus mirabilis | urinary tract infection | urease | fimbriae | bladder stones

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Control of innate and adaptive immunity by the inflammasome

Cited by 66 publications

References 65 publications

The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection

The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection

Lipopolysaccharide/adenosine triphosphate induces IL-1β and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells

Proteus mirabilis fimbriae- and urease-dependent clusters assemble in an extracellular niche to initiate bladder stone formation

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