Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation

V. Kaushal, R. Dye, P. Pakavathkumar, B. Foveau, J. Flores, B. Hyman, Bernardino Ghetti, B. H. Koller, A. C. LeBlanc

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1-/- and Casp1-/- mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-β-mediated neuroinflammation and Casp6-mediated axonal degeneration.

Original languageEnglish (US)
Pages (from-to)1676-1686
Number of pages11
JournalCell Death and Differentiation
Volume22
Issue number10
DOIs
StatePublished - Oct 9 2015

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Caspase 6
Inflammasomes
Caspase 1
Interleukin-1beta
Neurons
Proteins
Alzheimer Disease
Cell-Free System
Brain
Brain Diseases
Green Fluorescent Proteins
Neutralizing Antibodies
Serum
Interleukin-1
Small Interfering RNA

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. / Kaushal, V.; Dye, R.; Pakavathkumar, P.; Foveau, B.; Flores, J.; Hyman, B.; Ghetti, Bernardino; Koller, B. H.; LeBlanc, A. C.

In: Cell Death and Differentiation, Vol. 22, No. 10, 09.10.2015, p. 1676-1686.

Research output: Contribution to journalArticle

Kaushal, V. ; Dye, R. ; Pakavathkumar, P. ; Foveau, B. ; Flores, J. ; Hyman, B. ; Ghetti, Bernardino ; Koller, B. H. ; LeBlanc, A. C. / Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 10. pp. 1676-1686.
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AU - Foveau, B.

AU - Flores, J.

AU - Hyman, B.

AU - Ghetti, Bernardino

AU - Koller, B. H.

AU - LeBlanc, A. C.

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