Frontline Science: Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis

Rebecca M. Baron, Min Young Kwon, Ana P. Castano, Sailaja Ghanta, Dario F. Riascos-Bernal, Silvia Lopez-Guzman, Alvaro Andres Macias, Bonna Ith, Scott L. Schissel, James A. Lederer, Raymond Reeves, Shaw Fang Yet, Matthew D. Layne, Xiaoli Liu, Mark A. Perrella

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

High mobility group (HMG) proteins are a family of architectural transcription factors, with HMGA1 playing a role in the regulation of genes involved in promoting systemic inflammatory responses. We speculated that blocking HMGA1-mediated pathways might improve outcomes from sepsis. To investigate HMGA1 further, we developed genetically modified mice expressing a dominant negative (dn) form of HMGA1 targeted to the vasculature. In dnHMGA1 transgenic (Tg) mice, endogenous HMGA1 is present, but its function is decreased due to the mutant transgene. These mice allowed us to specifically study the importance of HMGA1 not only during a purely pro-inflammatory insult of endotoxemia, but also during microbial sepsis induced by implantation of a bacterial-laden fibrin clot into the peritoneum. We found that the dnHMGA1 transgene was only present in Tg and not wild-type (WT) littermate mice, and the mutant transgene was able to interact with transcription factors (such as NF-κB), but was not able to bind DNA. Tg mice exhibited a blunted hypotensive response to endotoxemia, and less mortality in microbial sepsis. Moreover, Tg mice had a reduced inflammatory response during sepsis, with decreased macrophage and neutrophil infiltration into tissues, which was associated with reduced expression of monocyte chemotactic protein-1 and macrophage inflammatory protein-2. Collectively, these data suggest that targeted expression of a dnHMGA1 transgene is able to improve outcomes in models of endotoxin exposure and microbial sepsis, in part by modulating the immune response and suggest a novel modifiable pathway to target therapeutics in sepsis.

Original languageEnglish (US)
Pages (from-to)677-689
Number of pages13
JournalJournal of Leukocyte Biology
Volume104
Issue number4
DOIs
StatePublished - Oct 2018

Fingerprint

Transgenes
Sepsis
Transgenic Mice
Endotoxemia
Transcription Factors
High Mobility Group Proteins
Chemokine CXCL2
Neutrophil Infiltration
Chemokine CCL2
Peritoneum
Fibrin
Endotoxins
Macrophages
Mortality
DNA
Genes

Keywords

  • architectural transcription factor
  • chemokines
  • immune response
  • transgenic mice

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Cite this

Frontline Science : Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis. / Baron, Rebecca M.; Kwon, Min Young; Castano, Ana P.; Ghanta, Sailaja; Riascos-Bernal, Dario F.; Lopez-Guzman, Silvia; Macias, Alvaro Andres; Ith, Bonna; Schissel, Scott L.; Lederer, James A.; Reeves, Raymond; Yet, Shaw Fang; Layne, Matthew D.; Liu, Xiaoli; Perrella, Mark A.

In: Journal of Leukocyte Biology, Vol. 104, No. 4, 10.2018, p. 677-689.

Research output: Contribution to journalArticle

Baron, RM, Kwon, MY, Castano, AP, Ghanta, S, Riascos-Bernal, DF, Lopez-Guzman, S, Macias, AA, Ith, B, Schissel, SL, Lederer, JA, Reeves, R, Yet, SF, Layne, MD, Liu, X & Perrella, MA 2018, 'Frontline Science: Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis', Journal of Leukocyte Biology, vol. 104, no. 4, pp. 677-689. https://doi.org/10.1002/JLB.4HI0817-333RR
Baron, Rebecca M. ; Kwon, Min Young ; Castano, Ana P. ; Ghanta, Sailaja ; Riascos-Bernal, Dario F. ; Lopez-Guzman, Silvia ; Macias, Alvaro Andres ; Ith, Bonna ; Schissel, Scott L. ; Lederer, James A. ; Reeves, Raymond ; Yet, Shaw Fang ; Layne, Matthew D. ; Liu, Xiaoli ; Perrella, Mark A. / Frontline Science : Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis. In: Journal of Leukocyte Biology. 2018 ; Vol. 104, No. 4. pp. 677-689.
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abstract = "High mobility group (HMG) proteins are a family of architectural transcription factors, with HMGA1 playing a role in the regulation of genes involved in promoting systemic inflammatory responses. We speculated that blocking HMGA1-mediated pathways might improve outcomes from sepsis. To investigate HMGA1 further, we developed genetically modified mice expressing a dominant negative (dn) form of HMGA1 targeted to the vasculature. In dnHMGA1 transgenic (Tg) mice, endogenous HMGA1 is present, but its function is decreased due to the mutant transgene. These mice allowed us to specifically study the importance of HMGA1 not only during a purely pro-inflammatory insult of endotoxemia, but also during microbial sepsis induced by implantation of a bacterial-laden fibrin clot into the peritoneum. We found that the dnHMGA1 transgene was only present in Tg and not wild-type (WT) littermate mice, and the mutant transgene was able to interact with transcription factors (such as NF-κB), but was not able to bind DNA. Tg mice exhibited a blunted hypotensive response to endotoxemia, and less mortality in microbial sepsis. Moreover, Tg mice had a reduced inflammatory response during sepsis, with decreased macrophage and neutrophil infiltration into tissues, which was associated with reduced expression of monocyte chemotactic protein-1 and macrophage inflammatory protein-2. Collectively, these data suggest that targeted expression of a dnHMGA1 transgene is able to improve outcomes in models of endotoxin exposure and microbial sepsis, in part by modulating the immune response and suggest a novel modifiable pathway to target therapeutics in sepsis.",
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AU - Ghanta, Sailaja

AU - Riascos-Bernal, Dario F.

AU - Lopez-Guzman, Silvia

AU - Macias, Alvaro Andres

AU - Ith, Bonna

AU - Schissel, Scott L.

AU - Lederer, James A.

AU - Reeves, Raymond

AU - Yet, Shaw Fang

AU - Layne, Matthew D.

AU - Liu, Xiaoli

AU - Perrella, Mark A.

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