Bistable Mathematical Model of Neutrophil Migratory Patterns After LPS-Induced Epigenetic Reprogramming

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dc.contributor.authorCiupe, Stanca M.en
dc.contributor.authorBoribong, Brittany P.en
dc.contributor.authorKadelka, Sarahen
dc.contributor.authorJones, Caroline N.en
dc.contributor.departmentMathematicsen
dc.date.accessioned2021-05-13T12:03:58Zen
dc.date.available2021-05-13T12:03:58Zen
dc.date.issued2021-02-23en
dc.description.abstractThe highly controlled migration of neutrophils toward the site of an infection can be altered when they are trained with lipopolysaccharides (LPS), with high dose LPS enhancing neutrophil migratory pattern toward the bacterial derived source signal and super-low dose LPS inducing either migration toward an intermediary signal or dysregulation and oscillatory movement. Empirical studies that use microfluidic chemotaxis-chip devices with two opposing chemoattractants showed differential neutrophil migration after challenge with different LPS doses. The epigenetic alterations responsible for changes in neutrophil migratory behavior are unknown. We developed two mathematical models that evaluate the mechanistic interactions responsible for neutrophil migratory decision-making when exposed to competing chemoattractants and challenged with LPS. The first model, which considers the interactions between the receptor densities of two competing chemoattractants, their kinases, and LPS, displayed bistability between high and low ratios of primary to intermediary chemoattractant receptor densities. In particular, at equilibrium, we observe equal receptor densities for low LPS (< 15ng/mL); and dominance of receptors for the primary chemoattractant for high LPS (> 15ng/mL). The second model, which included additional interactions with an extracellular signal-regulated kinase in both phosphorylated and non-phosphorylated forms, has an additional dynamic outcome, oscillatory dynamics for both receptors, as seen in the data. In particular, it found equal receptor densities in the absence of oscillation for super-low and high LPS challenge (< 0.4 and 1.1 <LPS< 375 ng/mL); equal receptor densities with oscillatory receptor dynamics for super-low LPS (0.5 < LPS< 1.1ng/mL); and dominance of receptors for the primary chemoattractant for super-high LPS (>376 ng/mL). Predicting the mechanisms and the type of external LPS challenge responsible for neutrophils migration toward pro-inflammatory chemoattractants, migration toward pro-tolerant chemoattractants, or oscillatory movement is necessary knowledge in designing interventions against immune diseases, such as sepsis.en
dc.description.notesSK and SC acknowledge funding from National Science Foundation grant No. 1813011. BB and CJ acknowledge funding from The National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM133610.en
dc.description.sponsorshipNational Science FoundationNational Science Foundation (NSF) [1813011]; National Institute of General Medical Sciences of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R35GM133610]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fgene.2021.633963en
dc.identifier.eissn1664-8021en
dc.identifier.other633963en
dc.identifier.pmid33708241en
dc.identifier.urihttp://hdl.handle.net/10919/103259en
dc.identifier.volume12en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectneutrophil migrationen
dc.subjectmathematical modelen
dc.subjectlipopolysaccharide (LPS)en
dc.subjectbistabilityen
dc.subjectcellular decision-makingen
dc.titleBistable Mathematical Model of Neutrophil Migratory Patterns After LPS-Induced Epigenetic Reprogrammingen
dc.title.serialFrontiers in Geneticsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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