The role of NLRP3 in traumatic brain injury and its regulation by pioglitazone

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  • 1 Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea; and
  • 2 Department of Neurosurgery, St. Vincent’s Hospital, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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OBJECTIVE

Perilesional edema is a predominant mechanism underlying secondary brain injury after traumatic brain injury (TBI). Perilesional edema is characterized by inflammation, production of proinflammatory cytokines, and migration of peripheral immune cells into the brain. The nucleotide-binding domain and leucine-rich repeat (NLR) family pyrin domain–containing 3 protein (NLRP3) is a key component of secondary injury. Pioglitazone regulates NLRP3 and other inflammatory cytokines. In the present study, the role of NLRP3 and the pharmacological effects of pioglitazone were investigated in animal TBI models.

METHODS

Brain contusion was induced in a weight drop model involving 3 groups of mice: C57 BL/6 (sham group), NLRP3 knockout (K/O group), and pioglitazone-treated mice (treatment group). The percentage of brain water content of the 3 groups of mice was compared over a period of time. Western blot, immunohistochemistry, and immunofluorescence analyses were conducted to investigate NLRP3-related inflammasomes and the effects of pioglitazone in the TBI models.

RESULTS

Brain edema was the highest on day 3 after TBI in the sham group. Brain edema in both the K/O and the treatment groups was lower than in the sham group. In Western blot, the expression of inflammasomes was higher after TBI in the sham group, but the expression of interleukin-1β, caspase-1, and NLRP3 was decreased significantly following treatment with pioglitazone. The expression of GFAP (glial fibrillary acidic protein) and Iba1 was decreased in both the K/O and treatment groups. In addition, confocal microscopy revealed a decrease in microglial cell and astrocyte activation following pioglitazone therapy.

CONCLUSIONS

The inflammasome NLRP3 plays a pivotal role in regulating cerebral edema and secondary inflammation. Interestingly, pioglitazone reduced cerebral edema and immune response after TBI by downregulating the effects of NLRP3. These results suggest that the clinical application of pioglitazone may be a neuroprotective strategy in TBI.

ABBREVIATIONS ERK = extracellular signal–responsive kinase; GFAP = glial fibrillary acidic protein; IL = interleukin; K/O = knockout; NF-κB = nuclear factor–kappa B; NLR = nucleotide-binding domain and leucine-rich repeat; NLRP3 = NLR family pyrin domain–containing 3 protein; TBI = traumatic brain injury.

Supplementary Materials

    • Supplementary Figs 1–4 and Tables 1–2 (PDF 2.07 MB)

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Contributor Notes

Correspondence Seung Ho Yang: St. Vincent’s Hospital, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Gyeonggi-Do, Republic of Korea. 72ysh@catholic.ac.kr.

INCLUDE WHEN CITING Published online September 27, 2019; DOI: 10.3171/2019.6.JNS1954.

H.J.Y. and J.E.L. contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

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