Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia

Abstract Inflammation underpins aspects of insulin resistance and dysglycemia. Microbiota-derived cell wall components such as muropeptides or endotoxin can trigger changes in host immunity and metabolism. Specific peptidoglycan motifs promote metabolic tissue inflammation, lipolysis and insulin res...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Brittany M. Duggan, Kevin P. Foley, Brandyn D. Henriksbo, Joseph F. Cavallari, Akhilesh K. Tamrakar, Jonathan D. Schertzer
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
Materias:
R
Q
Acceso en línea:https://doaj.org/article/871e61fb014940668cc76f5a7be0fbe9
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:871e61fb014940668cc76f5a7be0fbe9
record_format dspace
spelling oai:doaj.org-article:871e61fb014940668cc76f5a7be0fbe92021-12-02T11:52:36ZTyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia10.1038/s41598-017-01822-02045-2322https://doaj.org/article/871e61fb014940668cc76f5a7be0fbe92017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01822-0https://doaj.org/toc/2045-2322Abstract Inflammation underpins aspects of insulin resistance and dysglycemia. Microbiota-derived cell wall components such as muropeptides or endotoxin can trigger changes in host immunity and metabolism. Specific peptidoglycan motifs promote metabolic tissue inflammation, lipolysis and insulin resistance via Nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Receptor-interacting serine/threonine-protein kinase 2 (Ripk2) mediates Nod1-induced immunity, but the role of Ripk2 in metabolism is ill-defined. We hypothesized that Ripk2 was required for Nod1-mediated inflammation, lipolysis and dysglycemia. This is relevant because certain tyrosine kinase inhibitors (TKIs) inhibit Ripk2 and there is clinical evidence of TKIs lowering inflammation and blood glucose. Here, we showed that only a subset of TKIs known to inhibit Ripk2 attenuated Nod1 ligand-mediated adipocyte lipolysis. TKIs that inhibit Ripk2 decreased cytokine responses induced by Nod1-activating peptidoglycan, but not endotoxin in both metabolic and immune cells. Pre-treatment of adipocytes or macrophages with the TKI gefitinib inhibited Nod1-induced Cxcl1 and Il-6 secretion. Furthermore, treatment of mice with gefitinib prevented Nod1-induced glucose intolerance in vivo. Ripk2 was required for these effects on inflammation and metabolism, since Nod1-mediated cytokine and blood glucose changes were absent in Ripk2−/− mice. Our data show that specific TKIs used in cancer also inhibit Nod1-Ripk2 immunometabolism responses indicative of metabolic disease.Brittany M. DugganKevin P. FoleyBrandyn D. HenriksboJoseph F. CavallariAkhilesh K. TamrakarJonathan D. SchertzerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Brittany M. Duggan
Kevin P. Foley
Brandyn D. Henriksbo
Joseph F. Cavallari
Akhilesh K. Tamrakar
Jonathan D. Schertzer
Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia
description Abstract Inflammation underpins aspects of insulin resistance and dysglycemia. Microbiota-derived cell wall components such as muropeptides or endotoxin can trigger changes in host immunity and metabolism. Specific peptidoglycan motifs promote metabolic tissue inflammation, lipolysis and insulin resistance via Nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Receptor-interacting serine/threonine-protein kinase 2 (Ripk2) mediates Nod1-induced immunity, but the role of Ripk2 in metabolism is ill-defined. We hypothesized that Ripk2 was required for Nod1-mediated inflammation, lipolysis and dysglycemia. This is relevant because certain tyrosine kinase inhibitors (TKIs) inhibit Ripk2 and there is clinical evidence of TKIs lowering inflammation and blood glucose. Here, we showed that only a subset of TKIs known to inhibit Ripk2 attenuated Nod1 ligand-mediated adipocyte lipolysis. TKIs that inhibit Ripk2 decreased cytokine responses induced by Nod1-activating peptidoglycan, but not endotoxin in both metabolic and immune cells. Pre-treatment of adipocytes or macrophages with the TKI gefitinib inhibited Nod1-induced Cxcl1 and Il-6 secretion. Furthermore, treatment of mice with gefitinib prevented Nod1-induced glucose intolerance in vivo. Ripk2 was required for these effects on inflammation and metabolism, since Nod1-mediated cytokine and blood glucose changes were absent in Ripk2−/− mice. Our data show that specific TKIs used in cancer also inhibit Nod1-Ripk2 immunometabolism responses indicative of metabolic disease.
format article
author Brittany M. Duggan
Kevin P. Foley
Brandyn D. Henriksbo
Joseph F. Cavallari
Akhilesh K. Tamrakar
Jonathan D. Schertzer
author_facet Brittany M. Duggan
Kevin P. Foley
Brandyn D. Henriksbo
Joseph F. Cavallari
Akhilesh K. Tamrakar
Jonathan D. Schertzer
author_sort Brittany M. Duggan
title Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia
title_short Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia
title_full Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia
title_fullStr Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia
title_full_unstemmed Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia
title_sort tyrosine kinase inhibitors of ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/871e61fb014940668cc76f5a7be0fbe9
work_keys_str_mv AT brittanymduggan tyrosinekinaseinhibitorsofripk2attenuatebacterialcellwallmediatedlipolysisinflammationanddysglycemia
AT kevinpfoley tyrosinekinaseinhibitorsofripk2attenuatebacterialcellwallmediatedlipolysisinflammationanddysglycemia
AT brandyndhenriksbo tyrosinekinaseinhibitorsofripk2attenuatebacterialcellwallmediatedlipolysisinflammationanddysglycemia
AT josephfcavallari tyrosinekinaseinhibitorsofripk2attenuatebacterialcellwallmediatedlipolysisinflammationanddysglycemia
AT akhileshktamrakar tyrosinekinaseinhibitorsofripk2attenuatebacterialcellwallmediatedlipolysisinflammationanddysglycemia
AT jonathandschertzer tyrosinekinaseinhibitorsofripk2attenuatebacterialcellwallmediatedlipolysisinflammationanddysglycemia
_version_ 1718394994444730368