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...

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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:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/871e61fb014940668cc76f5a7be0fbe9
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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
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Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia

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