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Metabolic trade-offs in Neonatal sepsis triggered by TLR4 and TLR1/2 ligands result in unique dysfunctions in neural breathing circuits.
Joana Alves, Michele; Browe, Brigitte M; Carolina Rodrigues Dias, Ana; Torres, Juliet M; Zaza, Giuliana; Bangudi, Suzy; Blackburn, Jessica; Wang, Wesley; de Araujo Fernandes-Junior, Silvio; Fadda, Paolo; Toland, Amanda; Baer, Lisa A; Stanford, Kristin I; Czeisler, Catherine; Garcia, Alfredo J; Javier Otero, José.
Afiliação
  • Joana Alves M; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Browe BM; Institute for Integrative Physiology, Grossman Institute for Neuroscience Quantitative Biology and Human Behavior, The Neuroscience Institute, The University of Chicago, Chicago, IL, United States.
  • Carolina Rodrigues Dias A; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Torres JM; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Zaza G; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Bangudi S; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Blackburn J; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Wang W; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • de Araujo Fernandes-Junior S; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Fadda P; Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.
  • Toland A; Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States; Department of Cancer Biology and Genetics and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States.
  • Baer LA; Department of Cancer Biology and Genetics and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States.
  • Stanford KI; Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Czeisler C; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.
  • Garcia AJ; Institute for Integrative Physiology, Grossman Institute for Neuroscience Quantitative Biology and Human Behavior, The Neuroscience Institute, The University of Chicago, Chicago, IL, United States. Electronic address: ajgarcia3@uchicago.edu.
  • Javier Otero J; Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States. Electronic address: jose.otero@osumc.edu.
Brain Behav Immun ; 119: 333-350, 2024 Jul.
Article em En | MEDLINE | ID: mdl-38561095
ABSTRACT
Neonatal sepsis remains one of the leading causes of mortality in newborns. Several brainstem-regulated physiological processes undergo disruption during neonatal sepsis. Mechanistic knowledge gaps exist at the interplay between metabolism and immune activation to brainstem neural circuits and pertinent physiological functions in neonates. To delineate this association, we induced systemic inflammation either by TLR4 (LPS) or TLR1/2 (PAM3CSK4) ligand administration in postnatal day 5 mice (PD5). Our findings show that LPS and PAM3CSK4 evoke substantial changes in respiration and metabolism. Physiological trade-offs led to hypometabolic-hypothermic responses due to LPS, but not PAM3CSK4, whereas to both TLR ligands blunted respiratory chemoreflexes. Neuroinflammatory pathways modulation in brainstem showed more robust effects in LPS than PAM3CSK4. Brainstem neurons, microglia, and astrocyte gene expression analyses showed unique responses to TLR ligands. PAM3CSK4 did not significantly modulate gene expression changes in GLAST-1 positive brainstem astrocytes. PD5 pups receiving PAM3CSK4 failed to maintain a prolonged metabolic state repression, which correlated to enhanced gasping latency and impaired autoresuscitation during anoxic chemoreflex challenges. In contrast, LPS administered pups showed no significant changes in anoxic chemoreflex. Electrophysiological studies from brainstem slices prepared from pups exposed to either TLR4 or PAM3CSK4 showed compromised transmission between preBötzinger complex and Hypoglossal as an exclusive response to the TLR1/2 ligand. Spatial gene expression analysis demonstrated a region-specific modulation of PAM3CSK4 within the raphe nucleus relative to other anatomical sites evaluated. Our findings suggest that metabolic changes due to inflammation might be a crucial tolerance mechanism for neonatal sepsis preserving neural control of breathing.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tronco Encefálico / Lipopolissacarídeos / Receptor 1 Toll-Like / Receptor 2 Toll-Like / Receptor 4 Toll-Like / Sepse Neonatal / Animais Recém-Nascidos Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tronco Encefálico / Lipopolissacarídeos / Receptor 1 Toll-Like / Receptor 2 Toll-Like / Receptor 4 Toll-Like / Sepse Neonatal / Animais Recém-Nascidos Idioma: En Ano de publicação: 2024 Tipo de documento: Article