IL-33 mast cell axis is central in LL-37 induced bladder inflammation and pain in a murine interstitial cystitis model

Jensen, Mark Martin; Jia, Wanjian; Schults, Austin; Ye, Xiangyang; Prestwich, Glenn D.

doi:10.1016/j.cyto.2018.05.012

Cited by 16 publications

(10 citation statements)

References 48 publications

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“…Infiltration of inflammatory cells such as mast cells has also been observed (Pang et al, 1995a;Pang et al, 1995b;Yamada et al, 2000). Mast cell activation leads to the release of diverse inflammatory mediators, most importantly histamine (Shan et al, 2019), cytokines (Peeker et al, 2000;Martin Jensen et al, 2018), TNF-α (Furuta et al, 2018), reactive oxygen species (ROS) (Chelombitko et al, 2016), and ATP (Mansfield and Hughes, 2014).…”

Section: Introductionmentioning

confidence: 99%

P2X7 Receptor Blockade Protects Against Acrolein-Induced Bladder Damage: A Potential New Therapeutic Approach for the Treatment of Bladder Inflammatory Diseases

et al. 2021

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Inflammatory conditions of the urinary bladder have been shown to be associated with urothelial damage and loss of function. The purinergic P2X7 receptor has been implicated in several inflammatory conditions. The aim of this study was to investigate the role of the P2X7 receptor in acrolein-induced inflammatory damage using the porcine urinary bladder. For this purpose, an ex-vivo model of porcine urothelial damage induced by direct instillation of acrolein into the whole bladder lumen was used. To determine the role of the P2X7 receptor, the bladders were pre-incubated with a selective P2X7 receptor antagonist, A804598 (10 μM), for 1 h. The effects of the acrolein-induced urothelial damage on the bladder’s function were assessed by examining the bladder wall contractile response, structure changes, apoptosis, and oxidative stress in the bladder tissues. The acrolein treatment led to significant damage to the urothelium histology, tight junction expression, and contractile responses. Acrolein also induced apoptosis in the mucosa layer. All these acrolein-induced responses were attenuated by pre-treatment with the P2X7 receptor antagonist A804598. Acrolein also significantly induced DNA oxidation in the submucosal layer; however, the P2X7 receptor antagonism did not show any protective effect towards the acrolein-induced oxidative stress. These findings suggested that the P2X7 receptor is involved in the acrolein-induced damage to the urothelium; therefore, the P2X7 receptor antagonists may be a new therapeutic option for the treatment of bladder inflammation.

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Section: Introductionmentioning

confidence: 99%

P2X7 Receptor Blockade Protects Against Acrolein-Induced Bladder Damage: A Potential New Therapeutic Approach for the Treatment of Bladder Inflammatory Diseases

et al. 2021

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“…Many of these defense factors are subject to metabolic and hormonal regulation changes that occur during diabetes or pregnancy (39)(40)(41)(42). Additionally, recent studies suggest that some, if not all, of these factors play immunomodulatory roles in the bladder (43)(44)(45).…”

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confidence: 99%

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Patras

Coady

Babu

et al. 2020

mSphere

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Group B Streptococcus (GBS) causes frequent urinary tract infection (UTI) in susceptible populations, including individuals with type 2 diabetes and pregnant women; however, specific host factors responsible for increased GBS susceptibility in these populations are not well characterized. Here, we investigate cathelicidin, a cationic antimicrobial peptide, known to be critical for defense during UTI with uropathogenic Escherichia coli (UPEC). We observed a loss of antimicrobial activity of human and mouse cathelicidins against GBS and UPEC in synthetic urine and no evidence for increased cathelicidin resistance in GBS urinary isolates. Furthermore, we found that GBS degrades cathelicidin in a protease-dependent manner. Surprisingly, in a UTI model, cathelicidin-deficient (Camp−/−) mice showed decreased GBS burdens and mast cell recruitment in the bladder compared to levels in wild-type (WT) mice. Pharmacologic inhibition of mast cells reduced GBS burdens and histamine release in WT but not Camp−/− mice. Streptozotocin-induced diabetic mice had increased bladder cathelicidin production and mast cell recruitment at 24 h postinfection with GBS compared to levels in nondiabetic controls. We propose that cathelicidin is an important immune regulator but ineffective antimicrobial peptide against GBS in urine. Combined, our findings may in part explain the increased frequency of GBS UTI in diabetic and pregnant individuals. IMPORTANCE Certain populations such as diabetic individuals are at increased risk for developing urinary tract infections (UTI), although the underlying reasons for this susceptibility are not fully known. Additionally, diabetics are more likely to become infected with certain types of bacteria, such as group B Streptococcus (GBS). In this study, we find that an antimicrobial peptide called cathelicidin, which is thought to protect the bladder from infection, is ineffective in controlling GBS and alters the type of immune cells that migrate to the bladder during infection. Using a mouse model of diabetes, we observe that diabetic mice are more susceptible to GBS infection even though they also have more infiltrating immune cells and increased production of cathelicidin. Taken together, our findings identify this antimicrobial peptide as a potential contributor to increased susceptibility of diabetic individuals to GBS UTI.

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“…LL-37 is a cationic peptide produced in humans from its precursor molecule hCAP18 by kallikreins [ 72 ]. LL-37 is produced by epithelial cells of various tissues [ 72 , 73 ], and enhances the function of neutrophils, induces the production of inflammatory chemokines including IL-8, and induces tissue vascularization [ 74 ] by stimulating angiogenesis [ 75 ]. LL-37 can activate and degranulate LAD2 cells, a mast cell line, and hematopoietic CD34 + derived MCs expressing MrgX2, the receptor for LL-37 [ 76 ].…”

Section: Mast Cell Extracellular Trapsmentioning

confidence: 99%

Significance of Mast Cell Formed Extracellular Traps in Microbial Defense

Komi

Kuebler

2021

Clinic Rev Allerg Immunol

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Mast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense.

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IL-33 mast cell axis is central in LL-37 induced bladder inflammation and pain in a murine interstitial cystitis model

Cited by 16 publications

References 48 publications

P2X7 Receptor Blockade Protects Against Acrolein-Induced Bladder Damage: A Potential New Therapeutic Approach for the Treatment of Bladder Inflammatory Diseases

P2X7 Receptor Blockade Protects Against Acrolein-Induced Bladder Damage: A Potential New Therapeutic Approach for the Treatment of Bladder Inflammatory Diseases

Host Cathelicidin Exacerbates Group BStreptococcusUrinary Tract Infection

Significance of Mast Cell Formed Extracellular Traps in Microbial Defense

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