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Semaphorin 3F signaling actively retains neutrophils at sites of inflammation
Tracie Plant, … , Moira K.B. Whyte, Sarah R. Walmsley
Tracie Plant, … , Moira K.B. Whyte, Sarah R. Walmsley
Published March 19, 2020
Citation Information: J Clin Invest. 2020;130(6):3221-3237. https://doi.org/10.1172/JCI130834.
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Research Article Inflammation Pulmonology Article has an altmetric score of 12

Semaphorin 3F signaling actively retains neutrophils at sites of inflammation

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Abstract

Neutrophilic inflammation is central to disease pathogenesis, for example, in chronic obstructive pulmonary disease, yet the mechanisms that retain neutrophils within tissues remain poorly understood. With emerging evidence that axon guidance factors can regulate myeloid recruitment and that neutrophils can regulate expression of a class 3 semaphorin, SEMA3F, we investigated the role of SEMA3F in inflammatory cell retention within inflamed tissues. We observed that neutrophils upregulate SEMA3F in response to proinflammatory mediators and following neutrophil recruitment to the inflamed lung. In both zebrafish tail injury and murine acute lung injury models of neutrophilic inflammation, overexpression of SEMA3F delayed inflammation resolution with slower neutrophil migratory speeds and retention of neutrophils within the tissues. Conversely, constitutive loss of sema3f accelerated egress of neutrophils from the tail injury site in fish, whereas neutrophil-specific deletion of Sema3f in mice resulted in more rapid neutrophil transit through the airways, and significantly reduced time to resolution of the neutrophilic response. Study of filamentous-actin (F-actin) subsequently showed that SEMA3F-mediated retention is associated with F-actin disassembly. In conclusion, SEMA3F signaling actively regulates neutrophil retention within the injured tissues with consequences for neutrophil clearance and inflammation resolution.

Authors

Tracie Plant, Suttida Eamsamarng, Manuel A. Sanchez-Garcia, Leila Reyes, Stephen A. Renshaw, Patricia Coelho, Ananda S. Mirchandani, Jessie-May Morgan, Felix E. Ellett, Tyler Morrison, Duncan Humphries, Emily R. Watts, Fiona Murphy, Ximena L. Raffo-Iraolagoitia, Ailiang Zhang, Jenna L. Cash, Catherine Loynes, Philip M. Elks, Freek Van Eeden, Leo M. Carlin, Andrew J.W. Furley, Moira K.B. Whyte, Sarah R. Walmsley

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Figure 6

Exogenous SEMA3F retains recruited neutrophils at the injury site in a murine model of acute lung injury.

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Exogenous SEMA3F retains recruited neutrophils at the injury site in a m...
(A and B) Intratracheal (IT) recombinant SEMA3F (1 μM) was administered to C57BL/6 mice 24 hours after nebulized LPS challenge or PBS. Mice were then sacrificed at 48 and 72 hours and BAL was performed with differential apoptosis cell/neutrophil counts (A), or lungs were retained for fixed lung slice imaging (B). Lungs harvested for lung imaging were instilled with agarose gel, and fixed and stained with the endothelial marker CD31 (green) and the neutrophil marker S100A9 (red). Lungs were imaged by confocal microscopy (Zeiss LSM 880 with Airyscan) with 3D reconstruction and neutrophil position relative to the blood vessels was assigned using Imaris software version 9.1, with at least 80 neutrophils quantified per mouse. Data are mean ± SEM with individual data points from 4 independent experiments (n = 12). (C–E) Naive Catchup (IVM-RED;Lifeact-GFP) mice were sacrificed and lungs were instilled with agarose gel, precision sliced, and imaged by confocal microscopy for 90 minutes with addition of SEMA3F or PBS vehicle control at 30 minutes. Following treatment, neutrophil mean speed (C), maximum speed (D), and track straightness (directionality) (E) were measured and analyzed for 60 minutes using Imaris software version 9.1. Data are from 3 independent experiments (n = 3). Statistical analysis was by 2-way ANOVA and Sidak’s post hoc test (A and B) or paired t test (C–E). *P < 0.05; **P < 0.01; ****P < 0.0001.

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