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<p>Neutrophils defend against respiratory infections but cause acute lung injury (ALI) when excessively recruited to the lung. Early life environmental factors can shape lung development, but how they impact neutrophil recruitment is not known. We show that exposing newborn mice to hyperoxia increases the number of adult alveolar type 1 (AT1) epithelial cells expressing the proliferation marker Ki-67. Although these cells were not proliferating, they expressed high levels of chemokines that stimulated neutrophil recruitment and ALI when mice were infected with influenza A virus or exposed to lipopolysaccharide (LPS). Neutrophil recruitment and chemokine production were attenuated in Ki-67 hypomorph mice infected with virus or exposed to LPS and enhanced by genetically overexpressing Ki-67 in their lungs. Silencing Ki-67 in a mouse AT1-like cell line reduced basal and IL-1β stimulation of RelA/p65 and NF-κB-dependent transcription of the chemokines <i>Cxcl1</i> and <i>Cxcl5</i>. Our findings reveal a novel role for Ki-67 to modulate the intensity of epithelial pro-inflammatory signaling, controlling neutrophil recruitment. The severity of respiratory infections may be influenced by mitogens and environmental factors that increase the expression of Ki-67.</p>

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Ki-67 promotes inflammatory signaling governing neutrophil recruitment during respiratory infections

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月10日

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  • Min Yee,
  • Ravi Misra,
  • Sarah Vesecky,
  • Michael Barravecchia,
  • Rauf A Najar,
  • Arshad Rahman,
  • Gloria S Pryhuber,
  • David A Dean,
  • B Paige Lawrence,
  • Daniel Fisher,
  • Michael A O’Reilly

摘要

Neutrophils defend against respiratory infections but cause acute lung injury (ALI) when excessively recruited to the lung. Early life environmental factors can shape lung development, but how they impact neutrophil recruitment is not known. We show that exposing newborn mice to hyperoxia increases the number of adult alveolar type 1 (AT1) epithelial cells expressing the proliferation marker Ki-67. Although these cells were not proliferating, they expressed high levels of chemokines that stimulated neutrophil recruitment and ALI when mice were infected with influenza A virus or exposed to lipopolysaccharide (LPS). Neutrophil recruitment and chemokine production were attenuated in Ki-67 hypomorph mice infected with virus or exposed to LPS and enhanced by genetically overexpressing Ki-67 in their lungs. Silencing Ki-67 in a mouse AT1-like cell line reduced basal and IL-1β stimulation of RelA/p65 and NF-κB-dependent transcription of the chemokines Cxcl1 and Cxcl5. Our findings reveal a novel role for Ki-67 to modulate the intensity of epithelial pro-inflammatory signaling, controlling neutrophil recruitment. The severity of respiratory infections may be influenced by mitogens and environmental factors that increase the expression of Ki-67.