The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock

Ganapati H. Mahabeleshwar; Daiji Kawanami; Nikunj Sharma; Yoichi Takami; Guangjin Zhou; Hong Shi; Lalitha Nayak; Darwin Jeyaraj; Robert Grealy; Mary White; Ross McManus; Thomas Ryan; Patrick Leahy; Zhiyong Lin; Saptarsi M. Haldar; G. Brandon Atkins; Hector R. Wong; Jerry B. Lingrel; Mukesh K. Jain

doi:10.1016/j.immuni.2011.04.014

The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock

Ganapati H. Mahabeleshwar, Daiji Kawanami, Nikunj Sharma, Yoichi Takami, Guangjin Zhou, Hong Shi, Lalitha Nayak, Darwin Jeyaraj, Robert Grealy, Mary White, Ross McManus, Thomas Ryan, Patrick Leahy, Zhiyong Lin, Saptarsi M. Haldar, G. Brandon Atkins, Hector R. Wong, Jerry B. Lingrel, Mukesh K. Jain

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

112 Scopus citations

Abstract

Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.

Original language	English (US)
Pages (from-to)	715-728
Number of pages	14
Journal	Immunity
Volume	34
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2011.04.014
State	Published - May 27 2011
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2011.04.014

Cite this

Mahabeleshwar, G. H., Kawanami, D., Sharma, N., Takami, Y., Zhou, G., Shi, H., Nayak, L., Jeyaraj, D., Grealy, R., White, M., McManus, R., Ryan, T., Leahy, P., Lin, Z., Haldar, S. M., Atkins, G. B., Wong, H. R., Lingrel, J. B., & Jain, M. K. (2011). The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock. Immunity, 34(5), 715-728. https://doi.org/10.1016/j.immuni.2011.04.014

Mahabeleshwar, GH, Kawanami, D, Sharma, N, Takami, Y, Zhou, G, Shi, H, Nayak, L, Jeyaraj, D, Grealy, R, White, M, McManus, R, Ryan, T, Leahy, P, Lin, Z, Haldar, SM, Atkins, GB, Wong, HR, Lingrel, JB & Jain, MK 2011, 'The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock', Immunity, vol. 34, no. 5, pp. 715-728. https://doi.org/10.1016/j.immuni.2011.04.014

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title = "The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock",

abstract = "Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.",

author = "Mahabeleshwar, {Ganapati H.} and Daiji Kawanami and Nikunj Sharma and Yoichi Takami and Guangjin Zhou and Hong Shi and Lalitha Nayak and Darwin Jeyaraj and Robert Grealy and Mary White and Ross McManus and Thomas Ryan and Patrick Leahy and Zhiyong Lin and Haldar, {Saptarsi M.} and Atkins, {G. Brandon} and Wong, {Hector R.} and Lingrel, {Jerry B.} and Jain, {Mukesh K.}",

note = "Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grants HL72952, HL75427, HL76754, HL086548, HL084154, and P01 HL048743 (M.K.J.); HL097023 (G.H.M.); HL078806 (J.B.L.); HL087595 (Z.L.); HL088740 (G.B.A.); HL086614 (S.M.H.); HL094660 (D.J.); and GM064619 and HL100474 (H.R.W.); a Robert Wood Johnson/Harold Amos Medical Faculty Development grant (G.B.A.), a Dominic Visconsi Scholar Award (S.M.H., G.B.A.), American Heart Association Grants 0725297B (D.K.) and 09POST2060203 (N.S.), Sankyo Foundation of Life Science grants (Y.T.), and a Kanae Foundation for the Promotion of Medical Science grant (Y.T. and D.K.). ",

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AU - Mahabeleshwar, Ganapati H.

AU - Kawanami, Daiji

AU - Sharma, Nikunj

AU - Takami, Yoichi

AU - Zhou, Guangjin

AU - Shi, Hong

AU - Nayak, Lalitha

AU - Jeyaraj, Darwin

AU - Grealy, Robert

AU - White, Mary

AU - McManus, Ross

AU - Ryan, Thomas

AU - Leahy, Patrick

AU - Lin, Zhiyong

AU - Haldar, Saptarsi M.

AU - Atkins, G. Brandon

AU - Wong, Hector R.

AU - Lingrel, Jerry B.

AU - Jain, Mukesh K.

N1 - Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grants HL72952, HL75427, HL76754, HL086548, HL084154, and P01 HL048743 (M.K.J.); HL097023 (G.H.M.); HL078806 (J.B.L.); HL087595 (Z.L.); HL088740 (G.B.A.); HL086614 (S.M.H.); HL094660 (D.J.); and GM064619 and HL100474 (H.R.W.); a Robert Wood Johnson/Harold Amos Medical Faculty Development grant (G.B.A.), a Dominic Visconsi Scholar Award (S.M.H., G.B.A.), American Heart Association Grants 0725297B (D.K.) and 09POST2060203 (N.S.), Sankyo Foundation of Life Science grants (Y.T.), and a Kanae Foundation for the Promotion of Medical Science grant (Y.T. and D.K.).

PY - 2011/5/27

Y1 - 2011/5/27

N2 - Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.

AB - Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.

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The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock

Abstract

ASJC Scopus subject areas

UN SDGs

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