Balancing immune response: SHP1 controls neutrophil activation in inflamed lungs

J Clin Invest. 2024 Dec 16;134(24):e187056. doi: 10.1172/JCI187056.

Abstract

Following respiratory infection or injury, neutrophil hyperactivation can damage surrounding lung tissue by releasing harmful compounds. In this issue of the JCI, Moussavi-Harami and colleagues identified tyrosine phosphatase SHP1 as a key negative regulator of neutrophil activation in acute respiratory distress syndrome (ARDS). Neutrophil-specific Shp1 disruption leads to hyperinflammation, pulmonary hemorrhage, and increased mortality in both sterile and pathogen-induced acute lung injury (ALI). Large intravascular neutrophil clusters and excessive PAD4-independent neutrophil extracellular traps (NETs) were identified as key features of lung injury. Mechanistically, Shp1 deficiency resulted in uncontrolled SYK kinase activation, driving chaotic neutrophil hyperactivation and inflammation.

MeSH terms

  • Acute Lung Injury / immunology
  • Acute Lung Injury / pathology
  • Animals
  • Extracellular Traps / immunology
  • Humans
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Neutrophil Activation* / immunology
  • Neutrophils* / immunology
  • Neutrophils* / metabolism
  • Neutrophils* / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6* / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6* / immunology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6* / metabolism
  • Respiratory Distress Syndrome / immunology
  • Respiratory Distress Syndrome / pathology
  • Syk Kinase / immunology
  • Syk Kinase / metabolism

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse
  • Syk Kinase