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Purinergic Signaling to Terminate TLR Responses in Macrophages
Macrophages undergo profound physiological alterations when they encounter pathogen-associated molecular patterns (PAMPs). These alterations can result in the elaboration of cytokines and mediators that promote immune responses and contribute to the clearance of pathogens. These innate immune respon...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2016
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773587/ https://www.ncbi.nlm.nih.gov/pubmed/26973651 http://dx.doi.org/10.3389/fimmu.2016.00074 |
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author | Hamidzadeh, Kajal Mosser, David M. |
author_facet | Hamidzadeh, Kajal Mosser, David M. |
author_sort | Hamidzadeh, Kajal |
collection | PubMed |
description | Macrophages undergo profound physiological alterations when they encounter pathogen-associated molecular patterns (PAMPs). These alterations can result in the elaboration of cytokines and mediators that promote immune responses and contribute to the clearance of pathogens. These innate immune responses by myeloid cells are transient. The termination of these secretory responses is not due to the dilution of stimuli, but rather to the active downregulation of innate responses induced by the very PAMPs that initiated them. Here, we describe a purinergic autoregulatory program whereby TLR-stimulated macrophages control their activation state. In this program, TLR-stimulated macrophages undergo metabolic alterations that result in the production of ATP and its release through membrane pannexin channels. This purine nucleotide is rapidly hydrolyzed to adenosine by ectoenzymes on the macrophage surface, CD39 and CD73. Adenosine then signals through the P1 class of seven transmembrane receptors to induce a regulatory state that is characterized by the downregulation of inflammatory cytokines and the production of anti-inflammatory cytokines and growth factors. This purinergic autoregulatory system mitigates the collateral damage that would be caused by the prolonged activation of macrophages and rather allows the macrophage to maintain homeostasis. The transient activation of macrophages can be prolonged by treating macrophages with IFN-γ. IFN-γ-treated macrophages become less sensitive to the regulatory effects of adenosine, allowing them to sustain macrophage activation for the duration of an adaptive immune response. |
format | Online Article Text |
id | pubmed-4773587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-47735872016-03-11 Purinergic Signaling to Terminate TLR Responses in Macrophages Hamidzadeh, Kajal Mosser, David M. Front Immunol Immunology Macrophages undergo profound physiological alterations when they encounter pathogen-associated molecular patterns (PAMPs). These alterations can result in the elaboration of cytokines and mediators that promote immune responses and contribute to the clearance of pathogens. These innate immune responses by myeloid cells are transient. The termination of these secretory responses is not due to the dilution of stimuli, but rather to the active downregulation of innate responses induced by the very PAMPs that initiated them. Here, we describe a purinergic autoregulatory program whereby TLR-stimulated macrophages control their activation state. In this program, TLR-stimulated macrophages undergo metabolic alterations that result in the production of ATP and its release through membrane pannexin channels. This purine nucleotide is rapidly hydrolyzed to adenosine by ectoenzymes on the macrophage surface, CD39 and CD73. Adenosine then signals through the P1 class of seven transmembrane receptors to induce a regulatory state that is characterized by the downregulation of inflammatory cytokines and the production of anti-inflammatory cytokines and growth factors. This purinergic autoregulatory system mitigates the collateral damage that would be caused by the prolonged activation of macrophages and rather allows the macrophage to maintain homeostasis. The transient activation of macrophages can be prolonged by treating macrophages with IFN-γ. IFN-γ-treated macrophages become less sensitive to the regulatory effects of adenosine, allowing them to sustain macrophage activation for the duration of an adaptive immune response. Frontiers Media S.A. 2016-03-02 /pmc/articles/PMC4773587/ /pubmed/26973651 http://dx.doi.org/10.3389/fimmu.2016.00074 Text en Copyright © 2016 Hamidzadeh and Mosser. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Hamidzadeh, Kajal Mosser, David M. Purinergic Signaling to Terminate TLR Responses in Macrophages |
title | Purinergic Signaling to Terminate TLR Responses in Macrophages |
title_full | Purinergic Signaling to Terminate TLR Responses in Macrophages |
title_fullStr | Purinergic Signaling to Terminate TLR Responses in Macrophages |
title_full_unstemmed | Purinergic Signaling to Terminate TLR Responses in Macrophages |
title_short | Purinergic Signaling to Terminate TLR Responses in Macrophages |
title_sort | purinergic signaling to terminate tlr responses in macrophages |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773587/ https://www.ncbi.nlm.nih.gov/pubmed/26973651 http://dx.doi.org/10.3389/fimmu.2016.00074 |
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