TLR2-Induced IL-10 Production Impairs Neutrophil Recruitment to Infected Tissues during Neonatal Bacterial Sepsis

Andrade, Elva Bonifácio; Alves, Joana; Madureira, Pedro; Oliveira, Liliana; Ribeiro, Ana M.; Cordeiro-da-Silva, Anabela; Correia-Neves, Margarida; Trieu-Cuot, Patrick; Ferreira, Paula

doi:10.4049/jimmunol.1301752

Cited by 61 publications

(57 citation statements)

References 62 publications

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“…The LPS dose is one that previously sensitised the neonatal brain to HI brain injury [5]. We based the PAM dose on previous publications [9], as well as our own dose-response experiments from developing the model of PAM-sensitised HI brain injury [7]. The PAM model was developed to explore the neuroprotective effect of hypothermia after PAM-sensitised HI brain injury.…”

Section: Methodsmentioning

confidence: 99%

Neonatal Systemic Inflammation Induces Inflammatory Reactions and Brain Apoptosis in a Pathogen-Specific Manner

et al. 2017

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Background: After neonatal asphyxia, therapeutic hypothermia (HT) is the only proven treatment option. Although established as a neuroprotective therapy, benefit from HT has been questioned when infection is a comorbidity to hypoxic-ischaemic (HI) brain injury. Gram-negative and gram-positive species activate the immune system through different pathogen recognition receptors and subsequent immunological systems. In rodent models, gram-negative (lipopolysaccharide [LPS]) and gram-positive (PAM₃CSK₄ [PAM]) inflammation similarly increase neuronal vulnerability to HI. Interestingly, while LPS pre-sensitisation negates the neuroprotective effect of HT, HT is highly beneficial after PAM-sensitised HI brain injury. Objective: We aimed to examine whether systemic gram-positive or gram-negative inflammatory sensitisation affects juvenile rat pups per se, without an HI insult. Methods: Neonatal 7-day-old rats (n = 215) received intraperitoneal injections of vehicle (0.9% NaCl), LPS (0.1 mg/kg), or PAM (1 mg/kg). Core temperature and weight gain were monitored. Brain cytokine expression (IL-6, IL-1β, TNF-α, and IL-10, via PCR), apoptosis (cleaved caspase 3, via Western blots), and microglial activation (Iba1, via immunohistochemistry) were examined. Results: LPS induced an immediate drop in core temperature followed by poor weight gain, none of which were seen after PAM. Furthermore, LPS induced brain apoptosis, while PAM did not. The magnitude and temporal profile of brain cytokine expression differed between LPS- and PAM-injected animals. Conclusion: These findings reveal sepsis-like conditions and neuroinflammation specific to the inflammatory stimulus (gram-positive vs. gram-negative) in the neonatal rat. They emphasise the importance of pre-clinical models being pathogen dependent, and should always be carefully tailored to their clinical scenario.

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Section: Methodsmentioning

confidence: 99%

Neonatal Systemic Inflammation Induces Inflammatory Reactions and Brain Apoptosis in a Pathogen-Specific Manner

et al. 2017

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“…PAM was initially dissolved in sterile LPSfree water and then diluted in sterile physiological saline (0.9% NaCl). The dose of PAM was based on previous publications on this agonist used in neonatal rodents [28][29][30] , in combination with our own dose-response experiments (data not shown). Control groups received a single dose of sterile saline vehicle.…”

Section: Animals and Injectionsmentioning

confidence: 99%

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

et al. 2017

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Perinatal infection increases the vulnerability of the neonatal brain to hypoxic-ischaemic (HI) injury. Hypothermia treatment (HT) does not provide neuroprotection after pre-insult inflammatory sensitisation by lipopolysaccharide (LPS), a gram-negative bacterial wall constituent. However, early-onset sepsis in term babies is caused by gram-positive species in more than 90% of cases, and neuro-inflammatory responses triggered through the gram-negative route (Toll-like receptor 4, TLR-4) are different from those induced through the gram-positive route via TLR-2. Whether gram-positive septicaemia sensitises the neonatal brain to hypoxia and inhibits the neuroprotective effect of HT is unknown. Seven-day-old Wistar rats (n = 178) were subjected to intraperitoneal injections of PAM₃CSK₄ (1 mg/kg, a synthetic TLR-2 agonist) or vehicle (0.9% NaCl). After an 8-h delay, the left carotid artery was ligated followed by 50 min of hypoxia (8% O₂) at a rectal temperature of 36°C. Pups received a 5-h treatment of normothermia (NT, 37°C) or HT (32°C) immediately after the insult. Brains were harvested after 7 days' survival for hemispheric and hippocampal area loss analyses and immunolabelling of microglia (Iba1) and hippocampal neurons (NeuN). Normothermic PAM₃CSK₄-injected animals showed significantly more brain injury than vehicle animals (p = 0.014). Compared to NT, HT significantly reduced injury in the PAM₃CSK₄-injected animals, with reduced area loss (p < 0.001), reduced microglial activation (p = 0.006), and increased neuronal rescue in the CA1 region (p < 0.001). Experimental induction of a sepsis-like condition through the gram-positive pathway sensitises the brain to HI injury. HT was highly neuroprotective after the PAM₃CSK₄-triggered injury, suggesting HT may be neuroprotective in the presence of a gram-positive infection. These results are in strong contrast to LPS studies where HT is not neuroprotective.

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“…Especially in preterm infants monocytes may have an intrinsic deficiency to recognize and to respond to GBS [9]. One reason might be an impaired function of Toll-like receptors [10][11][12].…”

Section: Discussionmentioning

confidence: 99%

Septic Vs Colonizing Group B Streptococci Differentially Regulate Inflammation and Apoptosis in Human Coronary Artery Endothelial Cells - a Pilot Study

Loeffler¹

2015

JPNC

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TLR2-Induced IL-10 Production Impairs Neutrophil Recruitment to Infected Tissues during Neonatal Bacterial Sepsis

Cited by 61 publications

References 62 publications

Neonatal Systemic Inflammation Induces Inflammatory Reactions and Brain Apoptosis in a Pathogen-Specific Manner

Neonatal Systemic Inflammation Induces Inflammatory Reactions and Brain Apoptosis in a Pathogen-Specific Manner

Hypothermic Neuronal Rescue from Infection-Sensitised Hypoxic-Ischaemic Brain Injury Is Pathogen Dependent

Septic Vs Colonizing Group B Streptococci Differentially Regulate Inflammation and Apoptosis in Human Coronary Artery Endothelial Cells - a Pilot Study

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