Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa

Bielen, Kenny; Jongers, Bart ‘s; Boddaert, Jan; Raju, Tom Kalathil; Lammens, Christine; Malhotra-Kumar, Surbhi; Jorens, Philippe G.; Goossens, Herman; Kumar‐Singh, Samir

doi:10.3389/fcimb.2017.00274

Cited by 21 publications

(11 citation statements)

References 47 publications

(59 reference statements)

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“…Moreover, peripheral or central administration of M1 and M2 cells have also been shown to have beneficial, deleterious or no effect, suggesting that the evolution and functions of different subsets of microglia and brain macrophages in post-stroke brain are more complex than initially thought [ 15 , 39 , 40 ]. In this study, ≈50% of animals by day 3–4 developed pneumonia [ 24 , 25 ]. These data suggest that spontaneous development of infection due to stroke-induced immunosuppression, also shown earlier [ 13 ], is a major confounding factor for macrophage polarization studies.…”

Section: Discussionmentioning

confidence: 99%

“…Studies were performed on mixed gender Wistar rats aged 8–12 weeks with mean weight of 271 ± 39 g. Animals had ad libitum access to food and water before and after surgery and were housed in groups until 2 days before surgery, when they were housed individually. Animals that were febrile and/or showed histological evidence of pneumonia, as described by us previously [ 24 , 25 ], were excluded from the study. Animals belonged to sham or experimental stroke group (n = 6 per group for each study time point) and healthy control group (n = 6).…”

Section: Methodsmentioning

confidence: 99%

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CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

Boddaert¹,

Bielen²,

Jongers³

et al. 2018

PLoS ONE

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Classical or M1 activity of microglia/macrophages has been described in several neurodegenerative and brain inflammatory conditions and has also been linked to expansion of ischemic injury in post-stroke brain. While different pathways of M1 polarization have been suggested to occur in the post-stroke brain, the precise underlying mechanisms remain undefined. Using a transient middle cerebral artery occlusion (MCAO) rat model, we showed a progressive M2 to M1 polarization in the perilesional brain region with M1 cells becoming one of the dominant subsets by day 4 post-stroke. Comparing key receptors involved in M1 polarization (CD8, IFNγR, Clec4, FcγR, TLR3 and TLR4) and their signal transducers (Syk, Stat1, Irf3, and Traf6) at the day 4 time point, we showed a strong upregulation of CD8 along with SYK transducer in dissected perilesional brain tissue. We further showed that CD8 expression in the post-stroke brain was associated with activated (CD68+) macrophages and that progressive accumulation of CD8+CD68+ cells in the post-stroke brain coincided with increased iNOS (M1 marker) and reduced Arg1 (M2 marker) expression on these cells. In vitro ligand-based stimulation of the CD8 receptor caused increased iNOS expression and an enhanced capacity to phagocytose E. coli particles; and interestingly, CD8 stimulation was also able to repolarize IL4-treated M2 cells to an M1 phenotype. Our data suggest that increased CD8 signaling in the post-stroke brain is primarily associated with microglia/macrophages and can independently drive M1 polarization, and that modulation of CD8 signaling could be a potential target to limit secondary post-stroke brain damage.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

Boddaert¹,

Bielen²,

Jongers³

et al. 2018

PLoS ONE

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“…Biofilm-producing strains of P. aeruginosa are a major cause of morbidity and mortality in cystic fibrosis (CF) patients. In an animal model, increased levels of Th2 cytokines and macrophages were primarily EPS-driven rather than by the pathogen P. aeruginosa itself [73].…”

Section: Trends In Microbiologymentioning

confidence: 92%

Biofilm Matrixome: Extracellular Components in Structured Microbial Communities

Karygianni

Ren

Koo

et al. 2020

Trends in Microbiology

793

505

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Biofilms consist of microbial communities embedded in a 3D extracellular matrix. The matrix is composed of a complex array of extracellular polymeric substances (EPS) that contribute to the unique attributes of biofilm lifestyle and virulence. This ensemble of chemically and functionally diverse biomolecules is termed the 'matrixome'. The composition and mechanisms of EPS matrix formation, and its role in biofilm biology, function, and microenvironment are being revealed. This perspective article highlights recent advances about the multifaceted role of the 'matrixome' in the development, physical-chemical properties, and virulence of biofilms. We emphasize that targeting biofilm-specific conditions such as the matrixome could lead to precise and effective antibiofilm approaches. We also discuss the limited knowledge in the context of polymicrobial biofilms, and the need for more in-depth analyses of the EPS matrix in mixed communities that are associated with many human infectious diseases.

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“…RNA was converted to cDNA (RT2 First Strand Kit, Qiagen, Antwerp, Belgium) and quantitative PCR was performed on Bio-Rad CFX Connect with SsoAdvanced SYBR green supermix (Bio-Rad, Temse, Belgium) utilizing 2 step PCR with cycles of 95 °C for 10 s followed by 60 °C for 30 s. Primer sequences are shown in Table A1. Data were analyzed using the comparative CT method with Actb and Sdha as housekeeping genes as described earlier [7,47,48].…”

Section: Methodsmentioning

confidence: 99%

Mechanical Ventilation Impairs IL-17 Cytokine Family Expression in Ventilator-Associated Pneumonia

Winter

Jongers

Bielen

et al. 2019

IJMS

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Mechanical ventilation (MV) is the primary risk factor for the development of ventilator-associated pneumonia (VAP). Besides inducing a pro-inflammatory T-helper (Th)-1 cytokine response, MV also induces an anti-inflammatory Th2 cytokine response, marked by increased IL-4 secretion and reduced bacterial phagocytic capacity of rodent lung macrophages. Since IL-4 is known to downregulate both Th1 and Th17 cytokines, the latter is important in mediating mucosal immunity and combating bacterial and fungal growth, we studied and showed here in a rat model of MV that Th17 cytokines (IL-17A, IL-17F, and IL-22) were significantly upregulated in the lung as a response to different MV strategies currently utilized in clinic. To study whether the increased IL-4 levels are associated with downregulation of the anti-bacterial Th17 cytokines, we subsequently challenged mechanically ventilated rats with an intratracheal inoculation of Pseudomonas aeruginosa (VAP model) and showed a dramatic downregulation of IL-17A, IL-17F, and IL-22, compared to animals receiving the same bacterial burden without MV. For the studied Th1 cytokines (IFNγ, TNFα, IL-6, and IL-1β), only IFNγ showed a significant decrease as a consequence of bacterial infection in mechanically ventilated rats. We further studied IL-17A, the most studied IL-17 family member, in intensive care unit (ICU) pneumonia patients and showed that VAP patients had significantly lower levels of IL-17A in the endotracheal aspirate compared to patients entering ICU with pre-existing pneumonia. These translational data, obtained both in animal models and in humans, suggest that a deficient anti-bacterial Th17 response in the lung during MV is associated with VAP development.

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Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa

Cited by 21 publications

References 47 publications

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

Biofilm Matrixome: Extracellular Components in Structured Microbial Communities

Mechanical Ventilation Impairs IL-17 Cytokine Family Expression in Ventilator-Associated Pneumonia

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