Inhibition of histone deacetylase 6 restores innate immune cells in the bone marrow in a lethal septic model

Ting Zhao, Yongqing Li, Baoling Liu, Baihong Pan, Xin Cheng, Patrick Georgoff, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

BACKGROUND: We have previously demonstrated that Tubastatin A, a selective inhibitor of histone deacetylase 6 (HDAC6), improves survival and increases circulating monocyte count and bacterial clearance in a lethal model of cecal ligation and puncture (CLP) in mice. The aim of the present study was to characterize the effects of inhibition of HDAC6 on the bone marrow cell population. METHODS: C57BL/6J micewere subjected to CLP and, 1 hour later, given an intraperitoneal injection of either TubastatinA(70 mg/kg) dissolved in DMSO or DMSO alone (n = 9 per group). Sham-operated animals were treated in an identical fashion, without CLP. Forty-eight hours later, bone marrow cellswere flushed out from the femurs and tibias. Erythrocyteswere lysed, and a single-cell suspension was made for analysis. Cells were washed; blocked with antimouse CD16/32; stained with antimouse B220 PE-Cy7, CD3 APC-eFluor 780, CD11b FITC, Gr-1 PerCP-Cy5.5, and F4/80 Antigen APC; and subjected to flow cytometry. Data were acquired on an LSRII Flow Cytometer (BD Biosciences, San Jose, CA) and analyzed with FlowJo (Flowjo, LLC, Ashland, OR). RESULTS: In comparison with the sham group, CLP animals showed decreased percentage of innate immune cells (CD11b+, 62.1% T 3.1% vs. 32.9% T 4.9%, p = 0.0025) and macrophages (CD11b+F4/80+, 44.6% T 3.4% vs. 19.8% T 2.6%, p = 0.0002) as well as increased percentage of T lymphocytes (CD3+, 1.1% T 0.2% vs. 3.3% T 0.4%, p = 0.0082) in the bone marrow 48 hours after CLP. Treatment with TubastatinArestored the innate immune cells (32.9% T 4.9% vs. 54.0% T 4.1%, p = 0.0112) and macrophages (19.8% T 2.6% vs. 47.1% T 4.6%, p = 0.0001) and increased the percentage of neutrophils (CD11b+Gr-1+, 28.4% T 3.9% vs. 48.0% T 4.0%, p = 0.0075). The percentages of B (B220+) and T lymphocytes were not significantly altered by Tubastatin A, compared with the vehicle-treated CLP animals. CONCLUSION: Selective inhibition of HDAC6 in this lethal septic model restored the innate immune cell and macrophage populations and increased the neutrophil composition in the bone marrow. These results may explain the previously reported beneficial effects of Tubastatin A treatment in a septic model. J Trauma Acute Care Surg. 2016;80: 34-41.

Original languageEnglish (US)
Pages (from-to)34-41
Number of pages8
JournalJournal of Trauma and Acute Care Surgery
Volume80
Issue number1
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • Bone marrow
  • HDAC6
  • Innate immune cells
  • Mice
  • Sepsis

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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