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LETMD1 Regulates Phagocytosis and Inflammatory Responses to Lipopolysaccharide via Reactive Oxygen Species Generation and NF-κB Activation in Macrophages

Su-Geun Lim, Kyoungho Suk and Won-Ha Lee
J Immunol January 24, 2020, ji1900551; DOI: https://doi.org/10.4049/jimmunol.1900551
Su-Geun Lim
*School of Life Sciences, Brain Korea 21 Plus/Kyungpook National University Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; and
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Kyoungho Suk
†Department of Pharmacology, Brain Science and Engineering Institute, Brain Korea 21 Plus/Kyungpook National University Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea
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Won-Ha Lee
*School of Life Sciences, Brain Korea 21 Plus/Kyungpook National University Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; and
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Key Points

  • LETMD1 regulates phagocytosis and inflammatory responses in macrophages.

  • LETMD1 regulates NF-κB activities through mitochondrial hyperpolarization.

Abstract

LETM1 domain–containing protein 1 (LETMD1), also known as HCCR-1, is a mitochondrial protein and is known to regulate p53 and STAT3 activities in cancer cells. In this study, we present, for the first time (to our knowledge), data indicating that LETMD1 suppresses multiple immune responses in monocyte/macrophage lineage cells and mouse primary macrophages. Attenuation of LETMD1 expression with specific small interfering RNA and short hairpin RNA constructs enhanced LPS-induced expressions of inflammatory mediators in macrophages. In addition, LETMD1 attenuation caused potentiation of phagocytosis as well as migration in a macrophage-like cell line, U937. These enhancing effects were associated with altered activation of signaling adaptors (such as NF-κB, MAPKs, p53, and JAK-STAT) involved in TLR4 signaling. Especially, LETMD1 selectively regulated TLR4-induced NF-κB activation via MyD88 but not via TIR-domain–containing adapter-inducing IFN-β (TRIF). Attenuation of LETMD1 expression caused mitochondrial hyperpolarization and subsequent decrease in ATP production and increase in mitochondrial/cellular reactive oxygen species (ROS) and intracellular calcium levels. LETMD1 attenuation also enhanced LPS-induced expression of NADPH oxidase (NOX) 2, the main producer of cellular ROS in phagocytes, through augmenting IFN regulatory factor 1. Accordingly, treatment with ROS scavenger, NOX2 suppressing agents, or calcium chelators resulted in suppression of LPS-induced cytokine production as well as NF-κB activation in cells with LETMD1 attenuation. These findings reveal a previously unknown function of LETMD1 and provide evidences showing LETMD1 negatively regulates macrophage functions by modulating mitochondrial function, subsequent ROS generation, and NF-κB activation.

Footnotes

  • This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2017R1D1A1B04028358 and 2018R1A6A3A01011825).

  • The online version of this article contains supplemental material.

  • Received May 13, 2019.
  • Accepted December 23, 2019.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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LETMD1 Regulates Phagocytosis and Inflammatory Responses to Lipopolysaccharide via Reactive Oxygen Species Generation and NF-κB Activation in Macrophages
Su-Geun Lim, Kyoungho Suk, Won-Ha Lee
The Journal of Immunology January 24, 2020, ji1900551; DOI: 10.4049/jimmunol.1900551

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LETMD1 Regulates Phagocytosis and Inflammatory Responses to Lipopolysaccharide via Reactive Oxygen Species Generation and NF-κB Activation in Macrophages
Su-Geun Lim, Kyoungho Suk, Won-Ha Lee
The Journal of Immunology January 24, 2020, ji1900551; DOI: 10.4049/jimmunol.1900551
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Print ISSN 0022-1767        Online ISSN 1550-6606