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

## TL;DR

The study shows that Ki-67, a proliferation marker, modulates inflammation and neutrophil recruitment in the lungs during respiratory infections.

## Contribution

Ki-67 is newly identified as a modulator of pro-inflammatory signaling in lung epithelial cells, influencing neutrophil recruitment and lung injury.

## Key findings

- Neonatal hyperoxia increases Ki-67 expression in adult alveolar type 1 epithelial cells.
- Ki-67 hypomorph mice show reduced neutrophil recruitment and chemokine production during infection.
- Ki-67 enhances IL-1β regulation of chemokines like Cxcl1 and Cxcl5.

## Abstract

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.

This study identifies Ki-67 as a critical modulator of the intensity of pro-inflammatory gene expression governing neutrophil recruitment during respiratory infections. The severity of respiratory infections may be governed by mitogens and environmental factors that affect expression of Ki-67.

Ki-67 is a proliferation marker that organizes chromatin and thus the intensity of gene expression in a cell-specific manner.Neonatal hyperoxia increases the expression of Ki-67 in non-proliferating adult lung alveolar type 1 epithelial cells.Neutrophil recruitment is attenuated in Ki-67 hypomorph mice infected with influenza A virus or exposed to LPS and restored by genetically expressing Ki-67 in their lungs.Ki-67 increases the intensity of IL-1β regulation of chemokines that attract neutrophils to the lung.

Ki-67 is a proliferation marker that organizes chromatin and thus the intensity of gene expression in a cell-specific manner.

Neonatal hyperoxia increases the expression of Ki-67 in non-proliferating adult lung alveolar type 1 epithelial cells.

Neutrophil recruitment is attenuated in Ki-67 hypomorph mice infected with influenza A virus or exposed to LPS and restored by genetically expressing Ki-67 in their lungs.

Ki-67 increases the intensity of IL-1β regulation of chemokines that attract neutrophils to the lung.

This study identifies Ki-67 as a critical modulator of the intensity of pro-inflammatory gene expression governing neutrophil recruitment during respiratory infections. The severity of respiratory infections may be governed by mitogens and environmental factors that affect expression of Ki-67.