CD14 is a key organizer of microglial responses to CNS infection and injury

Hana Janova; Chotima Böttcher; Inge R. Holtman; Tommy Regen; Denise van Rossum; Alexander Götz; Anne Sophie Ernst; Christin Fritsche; Ulla Gertig; Nasrin Saiepour; Konrad Gronke; Claudia Wrzos; Sandra Ribes; Simone Rolfes; Jonathan Weinstein; Hannelore Ehrenreich; Tobias Pukrop; Jens Kopatz; Christine Stadelmann; Gabriela Salinas-Riester; Martin S. Weber; Marco Prinz; Wolfgang Brück; Bart J.L. Eggen; Hendrikus W.G.M. Boddeke; Josef Priller; Uwe Karsten Hanisch

doi:10.1002/glia.22955

CD14 is a key organizer of microglial responses to CNS infection and injury

Hana Janova, Chotima Böttcher, Inge R. Holtman, Tommy Regen, Denise van Rossum, Alexander Götz, Anne Sophie Ernst, Christin Fritsche, Ulla Gertig, Nasrin Saiepour, Konrad Gronke, Claudia Wrzos, Sandra Ribes, Simone Rolfes, Jonathan Weinstein, Hannelore Ehrenreich, Tobias Pukrop, Jens Kopatz, Christine Stadelmann, Gabriela Salinas-RiesterMartin S. Weber, Marco Prinz, Wolfgang Brück, Bart J.L. Eggen, Hendrikus W.G.M. Boddeke, Josef Priller, Uwe Karsten Hanisch

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

63 Scopus citations

Abstract

Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.

Original language	English
Pages (from-to)	635-649
Number of pages	15
Journal	GLIA
Volume	64
Issue number	4
DOIs	https://doi.org/10.1002/glia.22955
State	Published - 1 Apr 2016
Externally published	Yes

Keywords

Chemokines
Cytokines
Damage
Inflammation
Monocytes
Neutrophils
Toll-like receptor

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10.1002/glia.22955

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Janova, H., Böttcher, C., Holtman, I. R., Regen, T., van Rossum, D., Götz, A., Ernst, A. S., Fritsche, C., Gertig, U., Saiepour, N., Gronke, K., Wrzos, C., Ribes, S., Rolfes, S., Weinstein, J., Ehrenreich, H., Pukrop, T., Kopatz, J., Stadelmann, C., ... Hanisch, U. K. (2016). CD14 is a key organizer of microglial responses to CNS infection and injury. GLIA, 64(4), 635-649. https://doi.org/10.1002/glia.22955

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title = "CD14 is a key organizer of microglial responses to CNS infection and injury",

abstract = "Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.",

keywords = "Chemokines, Cytokines, Damage, Inflammation, Monocytes, Neutrophils, Toll-like receptor",

author = "Hana Janova and Chotima B{\"o}ttcher and Holtman, {Inge R.} and Tommy Regen and {van Rossum}, Denise and Alexander G{\"o}tz and Ernst, {Anne Sophie} and Christin Fritsche and Ulla Gertig and Nasrin Saiepour and Konrad Gronke and Claudia Wrzos and Sandra Ribes and Simone Rolfes and Jonathan Weinstein and Hannelore Ehrenreich and Tobias Pukrop and Jens Kopatz and Christine Stadelmann and Gabriela Salinas-Riester and Weber, {Martin S.} and Marco Prinz and Wolfgang Br{\"u}ck and Eggen, {Bart J.L.} and Boddeke, {Hendrikus W.G.M.} and Josef Priller and Hanisch, {Uwe Karsten}",

note = "Publisher Copyright: {\textcopyright} 2016 Wiley Periodicals, Inc.",

year = "2016",

month = apr,

day = "1",

doi = "10.1002/glia.22955",

language = "English",

volume = "64",

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Janova, H, Böttcher, C, Holtman, IR, Regen, T, van Rossum, D, Götz, A, Ernst, AS, Fritsche, C, Gertig, U, Saiepour, N, Gronke, K, Wrzos, C, Ribes, S, Rolfes, S, Weinstein, J, Ehrenreich, H, Pukrop, T, Kopatz, J, Stadelmann, C, Salinas-Riester, G, Weber, MS, Prinz, M, Brück, W, Eggen, BJL, Boddeke, HWGM, Priller, J & Hanisch, UK 2016, 'CD14 is a key organizer of microglial responses to CNS infection and injury', GLIA, vol. 64, no. 4, pp. 635-649. https://doi.org/10.1002/glia.22955

TY - JOUR

T1 - CD14 is a key organizer of microglial responses to CNS infection and injury

AU - Janova, Hana

AU - Böttcher, Chotima

AU - Holtman, Inge R.

AU - Regen, Tommy

AU - van Rossum, Denise

AU - Götz, Alexander

AU - Ernst, Anne Sophie

AU - Fritsche, Christin

AU - Gertig, Ulla

AU - Saiepour, Nasrin

AU - Gronke, Konrad

AU - Wrzos, Claudia

AU - Ribes, Sandra

AU - Rolfes, Simone

AU - Weinstein, Jonathan

AU - Ehrenreich, Hannelore

AU - Pukrop, Tobias

AU - Kopatz, Jens

AU - Stadelmann, Christine

AU - Salinas-Riester, Gabriela

AU - Weber, Martin S.

AU - Prinz, Marco

AU - Brück, Wolfgang

AU - Eggen, Bart J.L.

AU - Boddeke, Hendrikus W.G.M.

AU - Priller, Josef

AU - Hanisch, Uwe Karsten

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.

AB - Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.

KW - Chemokines

KW - Cytokines

KW - Damage

KW - Inflammation

KW - Monocytes

KW - Neutrophils

KW - Toll-like receptor

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U2 - 10.1002/glia.22955

DO - 10.1002/glia.22955

M3 - Article

C2 - 26683584

AN - SCOPUS:84958760537

SN - 0894-1491

VL - 64

SP - 635

EP - 649

JO - GLIA

JF - GLIA

IS - 4

ER -

CD14 is a key organizer of microglial responses to CNS infection and injury

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Keywords

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