Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection

Ching, Christina B.; Gupta, Shivani; Li, Birong; Cortado, Hanna; Mayne, Nicholas R.; Jackson, A Reeves; McHugh, Kirk M.; Becknell, Brian

doi:10.1016/j.kint.2017.12.006

Cited by 62 publications

(54 citation statements)

References 57 publications

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“…Knowing that IFN-γ can regulate IL-13 responses 30 , these observations indicated that following viral vector-based vaccination, at the cDC level the differential environmental immune responses to IL-13 are not only determined/regulated by STAT3/STAT6, but also by TGF-β1 and IFN-γ either collaboratively or independently, which was consistent with cancer/inflammation studies [53][54][55][56] . Interestingly, rapid STAT3 activation has shown to control some viral infections 51,57,58 whilst, STAT6 independent mechanisms have also been associated with effective antibody differentiation 28 . Moreover, IL-13 mediated enhanced IFN-γ signalling has been shown to exacerbate respiratory viral infections 31,59 .…”

Section: Discussionmentioning

confidence: 99%

Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination

Roy

Liu

Jaeson

et al. 2020

Sci Rep

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This study demonstrates that 24 h following viral vector-based vaccination IL-13Rα2 functions as a master sensor on conventional dendritic cells (cDCs), abetted by high protein stability coupled with minimal mRNA expression, to rapidly regulate DC mediated IL-13 responses at the lung mucosae, unlike IL-13Rα1. Under low IL-13, IL-13Rα2 performs as a primary signalling receptor, whilst under high IL-13, acts to sequester IL-13 to maintain homeostasis, both in a STAT3-dependent manner. Likewise, we show that viral vector-derived IL-13 levels at the vaccination site can induce differential STAT3/ STAT6 paradigms in lung cDC, that can get regulated collaboratively or independently by TGF-β1 and ifn-γ. Specifically, low IL-13 responses associated with recombinant Fowlpox virus (rFPV) is regulated by early IL-13Rα2, correlated with STAT3/TGF-β1 expression. Whilst, high IL-13 responses, associated with recombinant Modified Vaccinia Ankara (rMVA) is regulated in an IL-13Rα1/STAT6 dependent manner associated with IFN-γR expression bias. Different viral vaccine vectors have previously been shown to induce unique adaptive immune outcomes. Taken together current observations suggest that IL-13Rα2-driven STAT3/STAT6 equilibrium at the cDC level may play an important role in governing the efficacy of vector-based vaccines. These new insights have high potential to be exploited to improve recombinant viral vector-based vaccine design, according to the pathogen of interest and/or therapies against IL-13 associated disease conditions. IL-13 and IL-4 share a common signalling receptor system and are known to have overlapping as well as distinct functions 1. These two cytokines have been extensively studied under allergy, asthma, helminth and parasitic infections 2-5. IL-13 is produced by various immune cell types, specifically innate lymphoid cells (ILC2s), CD4 and CD8 T cells 6,7 and can directly impact the function of eosinophils, basophils and dendritic cells (DCs) 8,9. Recent allergy and asthma studies have shown that ILC2-derived IL-13 can stimulate the migration of lung DCs to promote Th2 immunity 10. Interestingly, whilst overproduction of IL-13 is associated with tissue pathology 11 , deficiency of IL-13 has been associated with increased susceptibility to certain skin cancers 12. Moreover, mounting evidence has also suggested the importance of IL-13 regulation in infection and immunity. We have previously demonstrated that the vaccine route, viral vector combination and cytokine milieu (level of IL-13) can significantly alter the adaptive immune outcomes 7,13,14. Pox viral vector-based HIV vaccine strategies that transiently inhibited IL-13 activity at the vaccination site, can induce high avidity/poly-functional T cells both in mice and macaques 15-17 (Li et al. in preparation). Interestingly, 24 h post delivery of these vaccines, whilst ILC2s were found to be the major source of IL-13 at the vaccination site 18 , elevated recruitment of CD11b + CD103 − conventional DCs (cDC) to the lung mucosae were associated with the o...

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Section: Discussionmentioning

confidence: 99%

Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination

Roy

Liu

Jaeson

et al. 2020

Sci Rep

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“…Pathogen recognition by urothelial cells has been suggested to stimulate IL-6 secretion 43 with key roles in limiting urothelial invasion and ascending infection. 44 Analysis by SPRING revealed strong upregulation of this molecule within the infected urothelium and topical inhibition by local intraurethral administration of antibodies against IL-6 aggravated the infection. Interestingly, the expression of IL-6 strongly correlates with bacterial burden in humans 45,46 and local production of IL-6 by urothelial cells was recently suggested.…”

Section: Discussionmentioning

confidence: 98%

Spatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder

et al. 2020

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The urothelium of the urinary bladder represents the first line of defense. However, uropathogenic E. coli (UPEC) damage the urothelium and cause acute bacterial infection. Here, we demonstrate the crosstalk between macrophages and the urothelium stimulating macrophage migration into the urothelium. Using spatial proteomics by MALDI-MSI and LC-MS/MS, a novel algorithm revealed the spatial activation and migration of macrophages. Analysis of the spatial proteome unravelled the coexpression of Myo9b and F4/80 in the infected urothelium, indicating that macrophages have entered the urothelium upon infection. Immunofluorescence microscopy additionally indicated that intraurothelial macrophages phagocytosed UPEC and eliminated neutrophils. Further analysis of the spatial proteome by MALDI-MSI showed strong expression of IL-6 in the urothelium and local inhibition of this molecule reduced macrophage migration into the urothelium and aggravated the infection. After IL-6 inhibition, the expression of matrix metalloproteinases and chemokines, such as CX 3 CL1 was reduced in the urothelium. Accordingly, macrophage migration into the urothelium was diminished in the absence of CX 3 CL1 signaling in Cx 3 cr1 gfp/gfp mice. Conclusively, this study describes the crosstalk between the infected urothelium and macrophages through IL-6-induced CX 3 CL1 expression. Such crosstalk facilitates the relocation of macrophages into the urothelium and reduces bacterial burden in the urinary bladder.Mucosal Immunology (2020) 13:702-714; https://doi.

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“…The MICs of 2Abz 23 S 29 and ciprofloxacin (cip) were determined by broth microdilution assay, according to a previously reported protocol. 17 In general, bacteria were grown overnight in LB for 24 h and were diluted to approximately 5 × 10 5 colony-forming units (CFU/mL) in Mueller Hinton Broth (MHB, Difco, Becton Dickinson Co., Sparks, MD, USA).…”

Section: Minimum Inhibitory Concentration (Mic) Assaymentioning

confidence: 99%

“…Interactions between ciprofloxacin (cip) and 2Abz 23 S 29 were studied by a broth microdilution checkerboard titration assay. Serial dilutions of ciprofloxacin were tested in the presence of serial dilutions of 2Abz 23 S 29 .…”

Section: Checkerboard Titration Assaymentioning

confidence: 99%

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A Synthetic Peptide 2Abz23S29 Reduces Bacterial Titer and Induces Pro-Inflammatory Cytokines in a Murine Model of Urinary Tract Infection

Moazzezy

Karam

Rafati

et al. 2020

DDDT

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Introduction: A urinary tract infection (UTI), which is often caused by uropathogenic E. coli (UPEC) strains, affects many people worldwide annually. UPEC causes the production of pro-inflammatory cytokines by the bladder epithelial cells; however, it has been proven that the UPEC can inhibit the early activation of the innate immune system. Methods: This study aimed to examine the antibacterial and immunomodulatory effects of different doses of truncated alpha-defensins (human neutrophil peptide (HNP)-1) analog 2Abz 23 S 29 on the mouse UTI model. Experimentally uropathogenic E. coli CFT073-infected mice were treated with low-dose 2Abz 23 S 29 (250µg/mL), high-dose 2Abz 23 S 29 (750µg/mL), ciprofloxacin (cip) (800µg/mL), or high-dose 2Abz 23 S 29 plus cip once a day 24 h postinfection. The 2Abz 23 S 29 and cip treatment were given for two consecutive days. Results: The in vivo results showed that fewer UPEC were recovered from the bladders of mice treated transurethrally with 2Abz 23 S 29. Moreover, low-dose 2Abz 23 S 29 significantly decreased the level of the interleukin-6 (IL-6), whereas high-dose 2Abz 23 S 29 increased pro-inflammatory cytokines including IL-6, macrophage inflammatory protein/2 (MIP/2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in infected bladders of mice. Besides, the levels of cytokines IL-6 and MIP/2 in infected mice treated with a combination of high-dose 2Abz 23 S 29 and cip were significantly higher than the untreated mice. In contrast, CFT073-infected mice treated with a combination of high-dose 2Abz 23 S 29 and cip showed no changes in cytokines TNF-α and IL-1β levels, indicating that ciprofloxacin may play an anti-inflammatory role. Conclusion: Collectively, apart from the direct antibacterial role of 2Abz 23 S 29 , our data illustrated that 2Abz 23 S 29 modulates pro-inflammatory cytokine production of bladder in a dosedependent manner, which has implications for the development of new anti-infective agents.

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Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection

Cited by 62 publications

References 57 publications

Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination

Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination

Spatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder

<p>A Synthetic Peptide 2Abz<sup>23</sup>S<sup>29</sup> Reduces Bacterial Titer and Induces Pro-Inflammatory Cytokines in a Murine Model of Urinary Tract Infection</p>

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