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Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes.

Ydens E, Demon D, Lornet G, De Winter V, Timmerman V, Lamkanfi M, Janssens S - J Neuroinflammation (2015)

Bottom Line: Loss of the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and effector caspase-1 and caspase-11 did not affect sciatic nerve function, suggesting that Nlrp6 contributed to recovery after peripheral nerve injury independently of inflammasomes.However, Nlrp6 deficiency was associated with increased pro-inflammatory extracellular regulated MAP kinase (ERK) signaling, suggesting that hyperinflammation in the absence of Nlrp6 exacerbated peripheral nerve injury.Together, our observations suggest that Nlrp6 contributes to recovery from peripheral nerve injury by dampening inflammatory responses independently of IL-1β and inflammasomes.

View Article: PubMed Central - PubMed

Affiliation: Peripheral Neuropathy Group, Department of Molecular Genetics, VIB and University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Antwerpen, Belgium. Elke.ydens@uhasselt.be.

ABSTRACT

Background: NOD-like receptors (Nlrs) are key regulators of immune responses during infection and autoimmunity. A subset of Nlrs assembles inflammasomes, molecular platforms that are activated in response to endogenous danger and microbial ligands and that control release of interleukin (IL)-1β and IL-18. However, their role in response to injury in the nervous system is less understood.

Methods: In this study, we investigated the expression profile of major inflammasome components in the peripheral nervous system (PNS) and explored the physiological role of different Nlrs upon acute nerve injury in mice.

Results: While in basal conditions, predominantly members of NOD-like receptor B (Nlrb) subfamily (NLR family, apoptosis inhibitory proteins (NAIPs)) and Nlrc subfamily (ICE-protease activating factor (IPAF)/NOD) are detected in the sciatic nerve, injury causes a shift towards expression of the Nlrp family. Sterile nerve injury also leads to an increase in expression of the Nlrb subfamily, while bacteria trigger expression of the Nlrc subfamily. Interestingly, loss of Nlrp6 led to strongly impaired nerve function upon nerve crush. Loss of the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and effector caspase-1 and caspase-11 did not affect sciatic nerve function, suggesting that Nlrp6 contributed to recovery after peripheral nerve injury independently of inflammasomes. In line with this, we did not detect release of mature IL-1β upon acute nerve injury despite potent induction of pro-IL-1β and inflammasome components Nlrp3 and Nlrp1. However, Nlrp6 deficiency was associated with increased pro-inflammatory extracellular regulated MAP kinase (ERK) signaling, suggesting that hyperinflammation in the absence of Nlrp6 exacerbated peripheral nerve injury.

Conclusions: Together, our observations suggest that Nlrp6 contributes to recovery from peripheral nerve injury by dampening inflammatory responses independently of IL-1β and inflammasomes.

No MeSH data available.


Related in: MedlinePlus

Nlr expression in primary Schwann cells, motor neurons, sensory neurons, peritoneal macrophages, and the sciatic nerve. a Nlr expression relative to the two most stable housekeeping genes out of five in the different primary cells, as determined by RT-qPCR. Note the different Y-axis scales used in the upper panel of each cell type. In the lower panel, the Y-axis is set to the same scale. In the graphs, the pooled data of three independent experiments is shown. b Ranking of Nlrs according to their relative expression levels in different PNS cell types as well as in the sciatic nerve, based on three to five independent experiments. − absent; +/− borderline detectable; +, ++, +++, ++++, +++++ indicate low to very strong expression
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Fig1: Nlr expression in primary Schwann cells, motor neurons, sensory neurons, peritoneal macrophages, and the sciatic nerve. a Nlr expression relative to the two most stable housekeeping genes out of five in the different primary cells, as determined by RT-qPCR. Note the different Y-axis scales used in the upper panel of each cell type. In the lower panel, the Y-axis is set to the same scale. In the graphs, the pooled data of three independent experiments is shown. b Ranking of Nlrs according to their relative expression levels in different PNS cell types as well as in the sciatic nerve, based on three to five independent experiments. − absent; +/− borderline detectable; +, ++, +++, ++++, +++++ indicate low to very strong expression

Mentions: As shown in Fig. 1a, b, several of the Nlrs tested in this study were expressed in the peripheral nerve and in the most common PNS cell types. The expression level was in general very low, as compared to macrophages (about 10–50×-fold less). Still, we could clearly detect cell-type-specific differences in the expression of Nlrs. Schwann cells expressed merely ASC, NAIP6, and NOD1. In sensory neurons, the Nlrb subfamily was overrepresented with major expression of NAIP1, NAIP5, and NAIP6 and lower expression of ASC and NOD1 (Fig. 1a, b). Motor neurons expressed very low levels of most Nlrs, and only ASC was clearly above detection limit. In the sciatic nerve, a compilation of those data could be seen and especially the Nlrb (NAIP) and Nlrc (IPAF/NOD) subfamilies and the adaptor protein ASC were highly expressed. In basal conditions, the Nlrp subfamily was less represented, although Nlrp1 and Nlrp3 were clearly detectable. Ranking of the different Nlrs according to their expression in the cell types or the nerve showed an almost identical expression pattern in Schwann cells and the peripheral nerve (Fig. 1b).Fig. 1


Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes.

Ydens E, Demon D, Lornet G, De Winter V, Timmerman V, Lamkanfi M, Janssens S - J Neuroinflammation (2015)

Nlr expression in primary Schwann cells, motor neurons, sensory neurons, peritoneal macrophages, and the sciatic nerve. a Nlr expression relative to the two most stable housekeeping genes out of five in the different primary cells, as determined by RT-qPCR. Note the different Y-axis scales used in the upper panel of each cell type. In the lower panel, the Y-axis is set to the same scale. In the graphs, the pooled data of three independent experiments is shown. b Ranking of Nlrs according to their relative expression levels in different PNS cell types as well as in the sciatic nerve, based on three to five independent experiments. − absent; +/− borderline detectable; +, ++, +++, ++++, +++++ indicate low to very strong expression
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4528710&req=5

Fig1: Nlr expression in primary Schwann cells, motor neurons, sensory neurons, peritoneal macrophages, and the sciatic nerve. a Nlr expression relative to the two most stable housekeeping genes out of five in the different primary cells, as determined by RT-qPCR. Note the different Y-axis scales used in the upper panel of each cell type. In the lower panel, the Y-axis is set to the same scale. In the graphs, the pooled data of three independent experiments is shown. b Ranking of Nlrs according to their relative expression levels in different PNS cell types as well as in the sciatic nerve, based on three to five independent experiments. − absent; +/− borderline detectable; +, ++, +++, ++++, +++++ indicate low to very strong expression
Mentions: As shown in Fig. 1a, b, several of the Nlrs tested in this study were expressed in the peripheral nerve and in the most common PNS cell types. The expression level was in general very low, as compared to macrophages (about 10–50×-fold less). Still, we could clearly detect cell-type-specific differences in the expression of Nlrs. Schwann cells expressed merely ASC, NAIP6, and NOD1. In sensory neurons, the Nlrb subfamily was overrepresented with major expression of NAIP1, NAIP5, and NAIP6 and lower expression of ASC and NOD1 (Fig. 1a, b). Motor neurons expressed very low levels of most Nlrs, and only ASC was clearly above detection limit. In the sciatic nerve, a compilation of those data could be seen and especially the Nlrb (NAIP) and Nlrc (IPAF/NOD) subfamilies and the adaptor protein ASC were highly expressed. In basal conditions, the Nlrp subfamily was less represented, although Nlrp1 and Nlrp3 were clearly detectable. Ranking of the different Nlrs according to their expression in the cell types or the nerve showed an almost identical expression pattern in Schwann cells and the peripheral nerve (Fig. 1b).Fig. 1

Bottom Line: Loss of the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and effector caspase-1 and caspase-11 did not affect sciatic nerve function, suggesting that Nlrp6 contributed to recovery after peripheral nerve injury independently of inflammasomes.However, Nlrp6 deficiency was associated with increased pro-inflammatory extracellular regulated MAP kinase (ERK) signaling, suggesting that hyperinflammation in the absence of Nlrp6 exacerbated peripheral nerve injury.Together, our observations suggest that Nlrp6 contributes to recovery from peripheral nerve injury by dampening inflammatory responses independently of IL-1β and inflammasomes.

View Article: PubMed Central - PubMed

Affiliation: Peripheral Neuropathy Group, Department of Molecular Genetics, VIB and University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Antwerpen, Belgium. Elke.ydens@uhasselt.be.

ABSTRACT

Background: NOD-like receptors (Nlrs) are key regulators of immune responses during infection and autoimmunity. A subset of Nlrs assembles inflammasomes, molecular platforms that are activated in response to endogenous danger and microbial ligands and that control release of interleukin (IL)-1β and IL-18. However, their role in response to injury in the nervous system is less understood.

Methods: In this study, we investigated the expression profile of major inflammasome components in the peripheral nervous system (PNS) and explored the physiological role of different Nlrs upon acute nerve injury in mice.

Results: While in basal conditions, predominantly members of NOD-like receptor B (Nlrb) subfamily (NLR family, apoptosis inhibitory proteins (NAIPs)) and Nlrc subfamily (ICE-protease activating factor (IPAF)/NOD) are detected in the sciatic nerve, injury causes a shift towards expression of the Nlrp family. Sterile nerve injury also leads to an increase in expression of the Nlrb subfamily, while bacteria trigger expression of the Nlrc subfamily. Interestingly, loss of Nlrp6 led to strongly impaired nerve function upon nerve crush. Loss of the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and effector caspase-1 and caspase-11 did not affect sciatic nerve function, suggesting that Nlrp6 contributed to recovery after peripheral nerve injury independently of inflammasomes. In line with this, we did not detect release of mature IL-1β upon acute nerve injury despite potent induction of pro-IL-1β and inflammasome components Nlrp3 and Nlrp1. However, Nlrp6 deficiency was associated with increased pro-inflammatory extracellular regulated MAP kinase (ERK) signaling, suggesting that hyperinflammation in the absence of Nlrp6 exacerbated peripheral nerve injury.

Conclusions: Together, our observations suggest that Nlrp6 contributes to recovery from peripheral nerve injury by dampening inflammatory responses independently of IL-1β and inflammasomes.

No MeSH data available.


Related in: MedlinePlus