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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 4

Neutrophil-driven deletion of Sema3f favors a selective allocation of neutrophils in the alveolar space while retaining antimicrobial capacity.

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Neutrophil-driven deletion of Sema3f favors a selective allocation of ne...
(A and B) Sema3ffl/flMrp8Cre–/– (WT) and Sema3ffl/flMrp8Cre+/– (KO) mice were challenged with nebulized LPS and sacrificed at 0, 2, and 6 hours following LPS challenge. Blood and lung tissues were harvested with lung digest for Ly6G staining (neutrophil number). In a parallel series of experiments, lungs were instilled with agarose gel at 6 hours, then 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 assigned, using Imaris software version 9.1 (neutrophil, white arrows) (C). Percentage of total neutrophils per 106 μm3 lung tissue is shown, with a minimum of 190 neutrophils quantified per mouse (D). Data are mean ± SEM from 3 individual experiments (n = 3–5). (E and F) WT and KO mice were challenged with intratracheal instillation of S. pneumoniae, and lung bacterial counts (E) and BAL and lung neutrophil counts (F) were undertaken 14 hours after challenge. Data are mean ± SEM from 2 individual experiments (n = 6–10). Statistical analysis was by 2-way ANOVA with Sidak’s post hoc test (A, B, and D) and Mann-Whitney (E) and 1-tailed unpaired t test (F). *P < 0.05.

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