Chemoattractant concentration–dependent tuning of ERK signaling dynamics in migrating neutrophils

Zhang, Elizabeth R.; Liu, Shanshan; Wu, Lani F.; Altschuler, Steven J.; Cobb, Melanie H.

doi:10.1126/scisignal.aag0486

Cited by 26 publications

(27 citation statements)

References 40 publications

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“…The next two most common pathways identified by Ingenuity in the ADU-HC comparison were related to IL17 signaling ( p = 1.94E-03) and Erk signaling ( p = 2.31E-03). IL17 signaling mediates numerous neutrophil-CD4+ T cells interactions, while Erk signaling is one of the primary regulators of neutrophil activation and chemotaxis 15 , 16 .…”

Section: Resultsmentioning

confidence: 99%

Modeling Transcriptional Rewiring in Neutrophils Through the Course of Treated Juvenile Idiopathic Arthritis

Jiang

Frank

et al. 2018

Sci Rep

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Neutrophils in children with the polyarticular form of juvenile idiopathic arthritis (JIA) display abnormal transcriptional patterns linked to fundamental metabolic derangements. In this study, we sought to determine the effects of therapy on mRNA and miRNA expression networks in polyarticular JIA. Using exon and miRNA microarrays, we studied children with untreated active JIA (ADU, n = 35), children with active disease on therapy with methotrexate ± etanercept (ADT, n = 26), and children with inactive disease also on therapy (ID, n = 14). We compared the results to findings from healthy control children (HC, n = 35). We found substantial re-ordering of mRNA and miRNA expression networks after the initiation of therapy. Each disease state was associated with a distinct transcriptional profile, with the ADT state differing the most from HC, and ID more strongly resembling HC. Changes at the mRNA level were mirrored in changes in miRNA expression patterns. The analysis of the expression dynamics from differentially expressed genes across three disease states indicated that therapeutic response is a complex process. This process does not simply involve genes slowly correcting in a linear fashion over time. Computational modeling of miRNA and transcription factor (TF) co-regulatory networks demonstrated that combinational regulation of miRNA and TF might play an important role in dynamic transcriptome changes.

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Section: Resultsmentioning

confidence: 99%

Modeling Transcriptional Rewiring in Neutrophils Through the Course of Treated Juvenile Idiopathic Arthritis

Jiang

Frank

et al. 2018

Sci Rep

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“…In other experiments, prior to exposure to FM-CM, neutrophils were pretreated for 30 min at 37˚C with either of the following: the NADPH oxidase inhibitor, diphenyleneiodonium (DPI; 10 mM; Sigma-Aldrich); the p38 MAP kinase inhibitor, SB203580 (1 mM; Selleckchem, Houston, TX); the ERK inhibitor, SCH772984 (10 nM; Selleckchem); or the JNK inhibitor, SP600125 (5 mM; Selleckchem). The dosages of inhibitors used have previously been reported to be effective in neutrophils (20,(28)(29)(30). The inhibitors were kept in the culture system during the whole treatment process through the media changes.…”

Section: Treatment Of Neutrophils With Fm-cmmentioning

confidence: 99%

Lipopolysaccharide-Stimulated Human Fetal Membranes Induce Neutrophil Activation and Release of Vital Neutrophil Extracellular Traps

Tong

Potter

Mor

et al. 2019

The Journal of Immunology

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Preterm birth is a major contributor to neonatal mortality and morbidity, and infection is a major risk factor. Chorioamnionitis, inflammation of the placenta, and fetal membranes (FMs) are commonly observed in preterm birth and are characterized by neutrophil infiltration. However, interactions between FMs and neutrophils remain incompletely understood. The objectives of this study were to determine how FMs, with or without bacterial LPS stimulation, affect neutrophil recruitment, activation, and the formation of neutrophil extracellular traps (NETs) and to elucidate the signaling mechanisms involved. Using a combination of in vitro, ex vivo, and in vivo approaches, we show that human resting FMs can directly recruit neutrophils and induce them to produce proinflammatory factors. Furthermore, neutrophils release vital NETs in response to FM-derived factors. LPS-stimulated FMs further augmented neutrophil recruitment, inflammatory cytokine/chemokine secretion, and vital NET release and also induced reactive oxygen species production and degranulation. We demonstrate a role for FM-derived TNF-a in mediating these effects through activation of neutrophil p38 MAPK. We propose that, during infection, neutrophil recruitment and activation may neutralize pathogens, vital NET formation, and prolonged neutrophil viability, and in combination with degranulation, reactive oxygen species production and inflammatory chemokine/cytokine production may contribute to tissue injury at the maternal/fetal interface.

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“…Next, we analyzed whether the fMLF-induced downstream signaling was impaired in JFC1 −/− neutrophils. Since Erk activation was recently shown to be required for neutrophil migration in response to fMLF, 40 we focused on Erk phosphorylation. In Fig.…”

Section: Fmlf-induced Actin Polymerization Calcium Signaling and Ermentioning

confidence: 99%

The trafficking protein JFC1 regulates Rac1-GTP localization at the uropod controlling neutrophil chemotaxis and in vivo migration

Ramadass

Johnson

Márki

et al. 2019

Journal of Leukocyte Biology

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Neutrophil chemotaxis is essential in responses to infection and underlies inflammation. In neutrophils, the small GTPase Rac1 has discrete functions at both the leading edge and in the retraction of the trailing structure at the cell's rear (uropod), but how Rac1 is regulated at the uropod is unknown. Here, we identified a mechanism mediated by the trafficking protein synaptotagmin‐like 1 (SYTL1 or JFC1) that controls Rac1‐GTP recycling from the uropod and promotes directional migration of neutrophils. JFC1‐null neutrophils displayed defective polarization and impaired directional migration to N‐formyl‐methionine‐leucyl‐phenylalanine in vitro, but chemoattractant‐induced actin remodeling, calcium signaling and Erk activation were normal in these cells. Defective chemotaxis was not explained by impaired azurophilic granule exocytosis associated with JFC1 deficiency. Mechanistically, we show that active Rac1 localizes at dynamic vesicles where endogenous JFC1 colocalizes with Rac1‐GTP. Super‐resolution microscopy (STORM) analysis shows adjacent distribution of JFC1 and Rac1‐GTP, which increases upon activation. JFC1 interacts with Rac1‐GTP in a Rab27a‐independent manner to regulate Rac1‐GTP trafficking. JFC1‐null cells exhibited Rac1‐GTP accumulation at the uropod and increased tail length, and Rac1‐GTP uropod accumulation was recapitulated by inhibition of ROCK or by interference with microtubule remodeling. In vivo, neutrophil dynamic studies in mixed bone marrow chimeric mice show that JFC1−/− neutrophils are unable to move directionally toward the source of the chemoattractant, supporting the notion that JFC1 deficiency results in defective neutrophil migration. Our results suggest that defective Rac1‐GTP recycling from the uropod affects directionality and highlight JFC1‐mediated Rac1 trafficking as a potential target to regulate chemotaxis in inflammation and immunity.

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Chemoattractant concentration–dependent tuning of ERK signaling dynamics in migrating neutrophils

Cited by 26 publications

References 40 publications

Modeling Transcriptional Rewiring in Neutrophils Through the Course of Treated Juvenile Idiopathic Arthritis

Modeling Transcriptional Rewiring in Neutrophils Through the Course of Treated Juvenile Idiopathic Arthritis

Lipopolysaccharide-Stimulated Human Fetal Membranes Induce Neutrophil Activation and Release of Vital Neutrophil Extracellular Traps

The trafficking protein JFC1 regulates Rac1-GTP localization at the uropod controlling neutrophil chemotaxis and in vivo migration

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