TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling
During inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases suc...
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doaj-7c8ee04e5a11479d9b310f0f5b3761342021-02-15T04:57:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011110.3389/fimmu.2020.606893606893TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR SignalingWiebke Nadolni0Roland Immler1Kilian Hoelting2Marco Fraticelli3Myriam Ripphahn4Simone Rothmiller5Masayuki Matsushita6Ingrid Boekhoff7Thomas Gudermann8Markus Sperandio9Susanna Zierler10Susanna Zierler11Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, GermanyWalter Brendel Centre of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, GermanyWalter Brendel Centre of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, Munich, GermanyBundeswehr Institute of Pharmacology and Toxicology, Munich, GermanyDepartment of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, JapanWalther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, GermanyWalter Brendel Centre of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, GermanyInstitute of Pharmacology, Johannes Kepler University Linz, Linz, AustriaDuring inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases such as rheumatoid arthritis. The transient-receptor-potential channel-kinase TRPM7 is an essential regulator of immune system homeostasis. Naïve murine T cells with genetic inactivation of the TRPM7 enzyme, due to a point mutation at the active site, are unable to differentiate into pro-inflammatory T cells, whereas regulatory T cells develop normally. Moreover, TRPM7 is vital for lipopolysaccharides (LPS)-induced activation of murine macrophages. Within this study, we show that the channel-kinase TRPM7 is functionally expressed in neutrophils and has an important impact on neutrophil recruitment during inflammation. We find that human neutrophils cannot transmigrate along a CXCL8 chemokine gradient or produce reactive oxygen species in response to gram-negative bacterial lipopolysaccharide LPS, if TRPM7 channel or kinase activity are blocked. Using a recently identified TRPM7 kinase inhibitor, TG100-115, as well as murine neutrophils with genetic ablation of the kinase activity, we confirm the importance of both TRPM7 channel and kinase function in murine neutrophil transmigration and unravel that TRPM7 kinase affects Akt1/mTOR signaling thereby regulating neutrophil transmigration and effector function. Hence, TRPM7 represents an interesting potential target to treat unwanted excessive neutrophil invasion.https://www.frontiersin.org/articles/10.3389/fimmu.2020.606893/fullTRPM7ion channelkinaseneutrophils (PMNs)innate immunityinflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wiebke Nadolni Roland Immler Kilian Hoelting Marco Fraticelli Myriam Ripphahn Simone Rothmiller Masayuki Matsushita Ingrid Boekhoff Thomas Gudermann Markus Sperandio Susanna Zierler Susanna Zierler |
spellingShingle |
Wiebke Nadolni Roland Immler Kilian Hoelting Marco Fraticelli Myriam Ripphahn Simone Rothmiller Masayuki Matsushita Ingrid Boekhoff Thomas Gudermann Markus Sperandio Susanna Zierler Susanna Zierler TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling Frontiers in Immunology TRPM7 ion channel kinase neutrophils (PMNs) innate immunity inflammation |
author_facet |
Wiebke Nadolni Roland Immler Kilian Hoelting Marco Fraticelli Myriam Ripphahn Simone Rothmiller Masayuki Matsushita Ingrid Boekhoff Thomas Gudermann Markus Sperandio Susanna Zierler Susanna Zierler |
author_sort |
Wiebke Nadolni |
title |
TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling |
title_short |
TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling |
title_full |
TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling |
title_fullStr |
TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling |
title_full_unstemmed |
TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling |
title_sort |
trpm7 kinase is essential for neutrophil recruitment and function via regulation of akt/mtor signaling |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-02-01 |
description |
During inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases such as rheumatoid arthritis. The transient-receptor-potential channel-kinase TRPM7 is an essential regulator of immune system homeostasis. Naïve murine T cells with genetic inactivation of the TRPM7 enzyme, due to a point mutation at the active site, are unable to differentiate into pro-inflammatory T cells, whereas regulatory T cells develop normally. Moreover, TRPM7 is vital for lipopolysaccharides (LPS)-induced activation of murine macrophages. Within this study, we show that the channel-kinase TRPM7 is functionally expressed in neutrophils and has an important impact on neutrophil recruitment during inflammation. We find that human neutrophils cannot transmigrate along a CXCL8 chemokine gradient or produce reactive oxygen species in response to gram-negative bacterial lipopolysaccharide LPS, if TRPM7 channel or kinase activity are blocked. Using a recently identified TRPM7 kinase inhibitor, TG100-115, as well as murine neutrophils with genetic ablation of the kinase activity, we confirm the importance of both TRPM7 channel and kinase function in murine neutrophil transmigration and unravel that TRPM7 kinase affects Akt1/mTOR signaling thereby regulating neutrophil transmigration and effector function. Hence, TRPM7 represents an interesting potential target to treat unwanted excessive neutrophil invasion. |
topic |
TRPM7 ion channel kinase neutrophils (PMNs) innate immunity inflammation |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2020.606893/full |
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