Innate Immune Training of Human Macrophages by Cathelicidin Analogs

Albert van Dijk; Jennifer Anten; Anne Bakker; Noah Evers; Anna T Hoekstra; Jung-Chin Chang; Maaike R Scheenstra; Edwin J A Veldhuizen; Mihai G Netea; Celia R Berkers; Henk P Haagsman

doi:10.3389/fimmu.2022.777530

Innate Immune Training of Human Macrophages by Cathelicidin Analogs

Albert van Dijk
, Jennifer Anten
, Anne Bakker
, Noah Evers
, Anna T Hoekstra
, Jung-Chin Chang
, Maaike R Scheenstra
, Edwin J A Veldhuizen
, Mihai G Netea
, Celia R Berkers
, Henk P Haagsman

Radboud University Medical Center

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.

Original language	English
Article number	777530
Pages (from-to)	1-18
Journal	Frontiers in Immunology
Volume	13
DOIs	https://doi.org/10.3389/fimmu.2022.777530
Publication status	Published - 26 Jul 2022

Bibliographical note

Funding Information:
We kindly thank Dr. Richard Wubbolts and Dr. Soledad Ordonez from the Center for Cell Imaging (CCI), Faculty of Veterinary Medicine, Utrecht University for analysis of confocal data, Miranda van Triest from Universitair Medisch Centrum Utrecht (UMC Utrecht) for assistance with the Seahorse assay and the Utrecht Sequencing Facility (USEQ) for providing sequencing service and data.

Funding Information:
This work was supported by the Dutch Ministry of Economic Affairs via the Immuno Valley Alternatives to Antibiotics (ALTANT) program (Animal-Specific Immunomodulatory Antimicrobials 2 project), NWO-TTW grant 14924 to the Bac-Vactory program and a TKI-LSH allowance grant (project no. LSHM18040). MN was supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research.

Publisher Copyright:
Copyright © 2022 van Dijk, Anten, Bakker, Evers, Hoekstra, Chang, Scheenstra, Veldhuizen, Netea, Berkers and Haagsman.

Keywords

Seahorse analysis
cathelicidin
host defense peptide
immunomodulation
macrophage
metabolomics
trained immunity

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Cite this

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title = "Innate Immune Training of Human Macrophages by Cathelicidin Analogs",

abstract = "Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.",

keywords = "Seahorse analysis, cathelicidin, host defense peptide, immunomodulation, macrophage, metabolomics, trained immunity",

author = "\{van Dijk\}, Albert and Jennifer Anten and Anne Bakker and Noah Evers and Hoekstra, \{Anna T\} and Jung-Chin Chang and Scheenstra, \{Maaike R\} and Veldhuizen, \{Edwin J A\} and Netea, \{Mihai G\} and Berkers, \{Celia R\} and Haagsman, \{Henk P\}",

note = "Funding Information: We kindly thank Dr. Richard Wubbolts and Dr. Soledad Ordonez from the Center for Cell Imaging (CCI), Faculty of Veterinary Medicine, Utrecht University for analysis of confocal data, Miranda van Triest from Universitair Medisch Centrum Utrecht (UMC Utrecht) for assistance with the Seahorse assay and the Utrecht Sequencing Facility (USEQ) for providing sequencing service and data. Funding Information: This work was supported by the Dutch Ministry of Economic Affairs via the Immuno Valley Alternatives to Antibiotics (ALTANT) program (Animal-Specific Immunomodulatory Antimicrobials 2 project), NWO-TTW grant 14924 to the Bac-Vactory program and a TKI-LSH allowance grant (project no. LSHM18040). MN was supported by an ERC Advanced Grant (\#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. Publisher Copyright: Copyright {\textcopyright} 2022 van Dijk, Anten, Bakker, Evers, Hoekstra, Chang, Scheenstra, Veldhuizen, Netea, Berkers and Haagsman.",

year = "2022",

month = jul,

day = "26",

doi = "10.3389/fimmu.2022.777530",

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AU - van Dijk, Albert

AU - Anten, Jennifer

AU - Bakker, Anne

AU - Evers, Noah

AU - Hoekstra, Anna T

AU - Chang, Jung-Chin

AU - Scheenstra, Maaike R

AU - Veldhuizen, Edwin J A

AU - Netea, Mihai G

AU - Berkers, Celia R

AU - Haagsman, Henk P

N1 - Funding Information: We kindly thank Dr. Richard Wubbolts and Dr. Soledad Ordonez from the Center for Cell Imaging (CCI), Faculty of Veterinary Medicine, Utrecht University for analysis of confocal data, Miranda van Triest from Universitair Medisch Centrum Utrecht (UMC Utrecht) for assistance with the Seahorse assay and the Utrecht Sequencing Facility (USEQ) for providing sequencing service and data. Funding Information: This work was supported by the Dutch Ministry of Economic Affairs via the Immuno Valley Alternatives to Antibiotics (ALTANT) program (Animal-Specific Immunomodulatory Antimicrobials 2 project), NWO-TTW grant 14924 to the Bac-Vactory program and a TKI-LSH allowance grant (project no. LSHM18040). MN was supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. Publisher Copyright: Copyright © 2022 van Dijk, Anten, Bakker, Evers, Hoekstra, Chang, Scheenstra, Veldhuizen, Netea, Berkers and Haagsman.

PY - 2022/7/26

Y1 - 2022/7/26

N2 - Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.

AB - Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.

KW - Seahorse analysis

KW - cathelicidin

KW - host defense peptide

KW - immunomodulation

KW - macrophage

KW - metabolomics

KW - trained immunity

UR - https://www.scopus.com/pages/publications/85135615404

U2 - 10.3389/fimmu.2022.777530

DO - 10.3389/fimmu.2022.777530

M3 - Article

C2 - 35958593

SN - 1664-3224

VL - 13

SP - 1

EP - 18

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 777530

ER -

Innate Immune Training of Human Macrophages by Cathelicidin Analogs

Abstract

Bibliographical note

Keywords

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