Abstract
ABSTRACTNeutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (MFN2) regulates neutrophil homeostasis and chemotaxis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue, trapped in the vasculature in zebrafish embryos, and not capable of chemotaxis. Consistent with this, human neutrophil-like cells that are deficient for MFN2 fail to arrest on activated endothelium under sheer stress or perform chemotaxis on 2D surfaces. Deletion of MFN2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mechanistically, MFN2-deficient neutrophil-like cells display disrupted mitochondria–ER interaction, heightened intracellular Ca2+ levels and elevated Rac activation after chemokine stimulation. Restoring a mitochondria–ER tether rescues the abnormal Ca2+ levels, Rac hyperactivation and chemotaxis defect resulting from MFN2 depletion. Finally, inhibition of Rac activation restores chemotaxis in MFN2-deficient neutrophils. Taken together, we have identified that MFN2 regulates neutrophil migration via maintaining the mitochondria–ER interaction to suppress Rac activation, and uncovered a previously unrecognized role of MFN2 in regulating cell migration and the actin cytoskeleton.This article has an associated First Person interview with the first authors of the paper.
Highlights
Neutrophils, the most abundant circulating leukocytes in humans, constitute the first line of host defense
This is in sharp contrast to what is seen in control or the wild-type embryos in which over 99% of neutrophils are retained in the caudal hematopoietic tissue or in the head mesenchyme (Harvie and Huttenlocher, 2015)
Circulating neutrophils were not observed in embryos expressing single-guide RNAs (sgRNAs) targeting opa1, the velocity of neutrophil migration in the head mesenchyme was significantly reduced (Fig. S1C,D; Movie 3), indicating that the decreased neutrophil retention in tissue is not due to defects in mitochondrial fusion
Summary
Neutrophils, the most abundant circulating leukocytes in humans, constitute the first line of host defense. Upon stimulation by either pathogen or host-derived proinflammatory mediators, neutrophils are recruited to inflamed tissue using spatially and temporally dynamic intracellular signaling pathways. G-protein-coupled receptors activate phospholipase C, which generates inositol 1,4,5-trisphosphate (IP3) and promotes Ca2+ release from intracellular stores (Tsai et al, 2015). Intracellular Ca2+ is a well-characterized second messenger that activates Rac and regulates cell migration in slowly migrating cells (Price et al, 2003), its role in Rac activation in neutrophils is less clear
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