Cargando…
A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4
The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which f...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AAI
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602158/ https://www.ncbi.nlm.nih.gov/pubmed/28807994 http://dx.doi.org/10.4049/jimmunol.1700377 |
_version_ | 1783264536606801920 |
---|---|
author | Jafarnejad, Mohammad Zawieja, David C. Brook, Bindi S. Nibbs, Robert J. B. Moore, James E. |
author_facet | Jafarnejad, Mohammad Zawieja, David C. Brook, Bindi S. Nibbs, Robert J. B. Moore, James E. |
author_sort | Jafarnejad, Mohammad |
collection | PubMed |
description | The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations. The mechanisms underpinning the establishment and regulation of these gradients are poorly understood. In this article, we have incorporated multiple biochemical processes describing the CCL19–CCL21–CCR7–ACKR4 network into our model of LN fluid flow to establish a computational model to investigate intranodal chemokine gradients. Importantly, the model recapitulates CCL21 gradients observed experimentally in B cell follicles and interfollicular regions, building confidence in its ability to accurately predict intranodal chemokine distribution. Parameter variation analysis indicates that the directionality of these gradients is robust, but their magnitude is sensitive to these key parameters: chemokine production, diffusivity, matrix binding site availability, and CCR7 abundance. The model indicates that lymph flow shapes intranodal CCL21 gradients, and that CCL19 is functionally important at the boundary between B cell follicles and the T cell area. It also predicts that ACKR4 in LNs prevents CCL19/CCL21 accumulation in efferent lymph, but does not control intranodal gradients. Instead, it attributes the disrupted interfollicular CCL21 gradients observed in Ackr4-deficient LNs to ACKR4 loss upstream. Our novel approach has therefore generated new testable hypotheses and alternative interpretations of experimental data. Moreover, it acts as a framework to investigate gradients at other locations, including those that cannot be visualized experimentally or involve other chemokines. |
format | Online Article Text |
id | pubmed-5602158 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | AAI |
record_format | MEDLINE/PubMed |
spelling | pubmed-56021582017-09-25 A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4 Jafarnejad, Mohammad Zawieja, David C. Brook, Bindi S. Nibbs, Robert J. B. Moore, James E. J Immunol Immune Regulation The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations. The mechanisms underpinning the establishment and regulation of these gradients are poorly understood. In this article, we have incorporated multiple biochemical processes describing the CCL19–CCL21–CCR7–ACKR4 network into our model of LN fluid flow to establish a computational model to investigate intranodal chemokine gradients. Importantly, the model recapitulates CCL21 gradients observed experimentally in B cell follicles and interfollicular regions, building confidence in its ability to accurately predict intranodal chemokine distribution. Parameter variation analysis indicates that the directionality of these gradients is robust, but their magnitude is sensitive to these key parameters: chemokine production, diffusivity, matrix binding site availability, and CCR7 abundance. The model indicates that lymph flow shapes intranodal CCL21 gradients, and that CCL19 is functionally important at the boundary between B cell follicles and the T cell area. It also predicts that ACKR4 in LNs prevents CCL19/CCL21 accumulation in efferent lymph, but does not control intranodal gradients. Instead, it attributes the disrupted interfollicular CCL21 gradients observed in Ackr4-deficient LNs to ACKR4 loss upstream. Our novel approach has therefore generated new testable hypotheses and alternative interpretations of experimental data. Moreover, it acts as a framework to investigate gradients at other locations, including those that cannot be visualized experimentally or involve other chemokines. AAI 2017-10-01 2017-08-14 /pmc/articles/PMC5602158/ /pubmed/28807994 http://dx.doi.org/10.4049/jimmunol.1700377 Text en Copyright © 2017 The Authors https://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the CC BY 4.0 Unported license. |
spellingShingle | Immune Regulation Jafarnejad, Mohammad Zawieja, David C. Brook, Bindi S. Nibbs, Robert J. B. Moore, James E. A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4 |
title | A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4 |
title_full | A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4 |
title_fullStr | A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4 |
title_full_unstemmed | A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4 |
title_short | A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4 |
title_sort | novel computational model predicts key regulators of chemokine gradient formation in lymph nodes and site-specific roles for ccl19 and ackr4 |
topic | Immune Regulation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602158/ https://www.ncbi.nlm.nih.gov/pubmed/28807994 http://dx.doi.org/10.4049/jimmunol.1700377 |
work_keys_str_mv | AT jafarnejadmohammad anovelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT zawiejadavidc anovelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT brookbindis anovelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT nibbsrobertjb anovelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT moorejamese anovelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT jafarnejadmohammad novelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT zawiejadavidc novelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT brookbindis novelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT nibbsrobertjb novelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 AT moorejamese novelcomputationalmodelpredictskeyregulatorsofchemokinegradientformationinlymphnodesandsitespecificrolesforccl19andackr4 |