Siglec-E Promotes beta 2-Integrin-dependent NADPH Oxidase Activation to Suppress Neutrophil Recruitment to the Lung

• Published in: The Journal of biological chemistry 2014-07, Vol.289 (29), p.20370-20376
• Main Authors: McMillan, Sarah J, Sharma, Ritu S, Richards, Hannah E, Hegde, Vikas, Crocker, Paul R
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.574624

Background: Siglec-E is a negative regulator of neutrophil recruitment to the lung in a mouse model of sepsis. Results: Siglec-E promotes integrin-dependent production of reactive oxygen species (ROS) and Akt activation. Conclusion: Siglec-E-promoted ROS plays a key role in its suppression of neutrophil recruitment to the lung. Significance: Siglecs may be new therapeutic targets in inflammatory lung disease. Siglec-E is a sialic acid-binding Ig-like lectin expressed on murine myeloid cells. It has recently been shown to function as a negative regulator of beta 2-integrin-dependent neutrophil recruitment to the lung following exposure to lipopolysaccharide (LPS). Here, we demonstrate that siglec-E promoted neutrophil production of reactive oxygen species (ROS) following CD11b beta 2-integrin ligation with fibrinogen in a sialic acid-dependent manner, but it had no effect on ROS triggered by a variety of other stimulants. Siglec-E promotion of ROS was likely mediated via Akt activation, because siglec-E-deficient neutrophils plated on fibrinogen exhibited reduced phosphorylation of Akt, and the Akt inhibitor, MK2206, blocked fibrinogen-induced ROS. In vivo imaging showed that siglec-E also promoted ROS in acutely inflamed lungs following exposure of mice to LPS. Importantly, siglec-E-promoted ROS were required for its inhibitory function, as the NADPH oxidase inhibitor, apocynin, reversed the siglec-E-mediated suppression of neutrophil recruitment and blocked neutrophil ROS production in vitro. Taken together, these results demonstrate that siglec-E functions as an inhibitory receptor of neutrophils via positive regulation of NADPH oxidase activation and ROS production. Our findings have implications for the inhibitory role of siglec-9 on human neutrophils in sepsis and acute lung injury.