Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice

The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and syst...

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Autores principales: Bonar, Sheri L., Brydges, Susannah D., Mueller, James L., McGeough, Matthew D., Pena, Carla, Chen, Debbie, Grimston, Susan K., Hickman-Brecks, Cynthia L., Ravindran, Soumya, McAlinden, Audrey, Novack, Deborah V., Kastner, Daniel L., Civitelli, Roberto, Hoffman, Hal M., Mbalaviele, Gabriel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338787/
https://www.ncbi.nlm.nih.gov/pubmed/22558291
http://dx.doi.org/10.1371/journal.pone.0035979
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author Bonar, Sheri L.
Brydges, Susannah D.
Mueller, James L.
McGeough, Matthew D.
Pena, Carla
Chen, Debbie
Grimston, Susan K.
Hickman-Brecks, Cynthia L.
Ravindran, Soumya
McAlinden, Audrey
Novack, Deborah V.
Kastner, Daniel L.
Civitelli, Roberto
Hoffman, Hal M.
Mbalaviele, Gabriel
author_facet Bonar, Sheri L.
Brydges, Susannah D.
Mueller, James L.
McGeough, Matthew D.
Pena, Carla
Chen, Debbie
Grimston, Susan K.
Hickman-Brecks, Cynthia L.
Ravindran, Soumya
McAlinden, Audrey
Novack, Deborah V.
Kastner, Daniel L.
Civitelli, Roberto
Hoffman, Hal M.
Mbalaviele, Gabriel
author_sort Bonar, Sheri L.
collection PubMed
description The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling.
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spelling pubmed-33387872012-05-03 Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice Bonar, Sheri L. Brydges, Susannah D. Mueller, James L. McGeough, Matthew D. Pena, Carla Chen, Debbie Grimston, Susan K. Hickman-Brecks, Cynthia L. Ravindran, Soumya McAlinden, Audrey Novack, Deborah V. Kastner, Daniel L. Civitelli, Roberto Hoffman, Hal M. Mbalaviele, Gabriel PLoS One Research Article The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling. Public Library of Science 2012-04-27 /pmc/articles/PMC3338787/ /pubmed/22558291 http://dx.doi.org/10.1371/journal.pone.0035979 Text en Bonar et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bonar, Sheri L.
Brydges, Susannah D.
Mueller, James L.
McGeough, Matthew D.
Pena, Carla
Chen, Debbie
Grimston, Susan K.
Hickman-Brecks, Cynthia L.
Ravindran, Soumya
McAlinden, Audrey
Novack, Deborah V.
Kastner, Daniel L.
Civitelli, Roberto
Hoffman, Hal M.
Mbalaviele, Gabriel
Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice
title Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice
title_full Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice
title_fullStr Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice
title_full_unstemmed Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice
title_short Constitutively Activated NLRP3 Inflammasome Causes Inflammation and Abnormal Skeletal Development in Mice
title_sort constitutively activated nlrp3 inflammasome causes inflammation and abnormal skeletal development in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338787/
https://www.ncbi.nlm.nih.gov/pubmed/22558291
http://dx.doi.org/10.1371/journal.pone.0035979
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