Journal
FRONTIERS IN PHARMACOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.584184
Keywords
acute nerve injury; motor neuron; neuroinflammation; inflammasome; nucleotide-binding oligomerization domain-; LRR; and pyrin domain-containing protein 3; diazoxide
Categories
Funding
- NKFIH(National Research, Development and Innovation Office) [GINOP-2.3.2-152016-00001, GINOP-2.3.2-15-2016-00034, GINOP-2.3.2-15-201600020, FK-124114, K-135425, K-135475]
- New National Excellence Program of the Ministry for Innovation and Technology of Hungary [UNKP-19-2-SZTE-92, UNKP-20-2-SZTE-68, UNKP-20-4SZTE-138]
- National Talent Program of the Hungarian Ministry of Human Capacities [NTP-NFTO-20-B-0192]
- Szeged Scientists Academy under Hungarian Ministry of Human Capacities [EMMI:11136-2/2019/FIRFIN]
- UEFISCDI (Executive Agency for Higher Education, Research, Development and Innovation) [PN-III-P1-1.1-TE-2019-1302]
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Neuronal injuries are accompanied by release and accumulation of damage-associated molecules, which in turn may contribute to activation of the immune system. Since a wide range of danger signals (including endogenous ones) are detected by the nucleotide-binding oligomerization domain-, LRR- and pyrin domain-containing protein 3 (NLRP3) pattern recognition receptor, we hypothesized that NLRP3 may become activated in response to motor neuron injury. Here we show that peripheral injury of the oculomotor and the hypoglossal nerves results in upregulation of NLRP3 in corresponding motor nuclei in the brainstem of mice. Although basal expression of NLRP3 was observed in microglia, astroglia and neurons as well, its upregulation and co-localization with apoptosis-associated speck-like protein containing a caspase activation and recruitment domain, suggesting inflammasome activation, was only detected in neurons. Consequently, increased production of active pro-inflammatory cytokines interleukin-1 beta and interleukin-18 were detected after hypoglossal nerve axotomy. Injury-sensitive hypoglossal neurons responded with a more pronounced NLRP3 upregulation than injury-resistant motor neurons of the oculomotor nucleus. We further demonstrated that the mitochondrial protector diazoxide was able to reduce NLRP3 upregulation in a post-operative treatment paradigm. Our results indicate that NLRP3 is activated in motoneurons following acute nerve injury. Blockade of NLRP3 activation might contribute to the previously observed anti-inflammatory and neuroprotective effects of diazoxide.
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