Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo. Front Immunol 2022;13:1061544
Date
12/13/2022Pubmed ID
36505495Pubmed Central ID
PMC9733537DOI
10.3389/fimmu.2022.1061544Scopus ID
2-s2.0-85143788625 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
INTRODUCTION: Neutrophils are critical for host immune defense; yet, aberrant neutrophil tissue infiltration triggers tissue damage. Neutrophils are heterogeneous functionally, and adopt 'normal' or 'pathogenic' effector function responses. Understanding neutrophil heterogeneity could provide specificity in targeting inflammation. We previously identified a signaling pathway that suppresses neutrophilmediated inflammation via integrin-mediated Rap1b signaling pathway.
METHODS: Here, we used Rap1-deficient neutrophils and proteomics to identify pathways that specifically control pathogenic neutrophil effector function.
RESULTS: We show neutrophil acidity is normally prevented by Rap1b during normal immune response with loss of Rap1b resulting in increased neutrophil acidity via enhanced Ldha activity and abnormal neutrophil behavior. Acidity drives the formation of abnormal invasive-like protrusions in neutrophils, causing a shift to transcellular migration through endothelial cells. Acidity increases neutrophil extracellular matrix degradation activity and increases vascular leakage in vivo. Pathogenic inflammatory condition of ischemia/reperfusion injury is associated with increased neutrophil transcellular migration and vascular leakage. Reducing acidity with lactate dehydrogenase inhibition in vivo limits tissue infiltration of pathogenic neutrophils but less so of normal neutrophils, and reduces vascular leakage.
DISCUSSION: Acidic milieu renders neutrophils more dependent on Ldha activity such that their effector functions are more readily inhibited by small molecule inhibitor of Ldha activity, which offers a therapeutic window for antilactate dehydrogenase treatment in specific targeting of pathogenic neutrophils in vivo.
Author List
Chowdhury CS, Wareham E, Xu J, Kumar S, Kofron M, Lakshmikanthan S, Chrzanowska M, Filippi MDAuthor
Magdalena Chrzanowska PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell MovementEndothelial Cells
Humans
Inflammation
L-Lactate Dehydrogenase
Neutrophil Infiltration
Neutrophils
rap GTP-Binding Proteins
