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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

Induction profile of immune mediators upon acute injury of the sciatic nerve. a Induction of IL-1 family members upon injury of the sciatic nerve, as shown by RT-qPCR analysis. b Induction of chemokines (MIP-1α and MCP-1) and cytokines (IL-6 and TNF) at different time points upon injury of the sciatic nerve. Data is analyzed using the ΔΔCt method, and mRNA expression levels are expressed relative to the basal condition (0-h time point). The graphs show the pooled data of five independent experiments (mean ± SD)
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Fig2: Induction profile of immune mediators upon acute injury of the sciatic nerve. a Induction of IL-1 family members upon injury of the sciatic nerve, as shown by RT-qPCR analysis. b Induction of chemokines (MIP-1α and MCP-1) and cytokines (IL-6 and TNF) at different time points upon injury of the sciatic nerve. Data is analyzed using the ΔΔCt method, and mRNA expression levels are expressed relative to the basal condition (0-h time point). The graphs show the pooled data of five independent experiments (mean ± SD)

Mentions: Next, we addressed whether Nlrs are regulated in the peripheral nerve upon inflammation. Sterile injury was induced by axotomy of the sciatic nerve. At different time points after the injury, the distal segment of the sciatic nerve was isolated; total RNA was isolated, converted to cDNA, and analyzed by RT-qPCR. The contralateral side was used as a control. We first analyzed the transcriptional regulation of the most established members of the IL-1 superfamily: IL-1α, IL-1β, IL-18, and IL-1 receptor antagonist (IL-1ra). Both IL-1β and the antagonist were highly induced already 4 h after injury (Fig. 2a). IL-1α was only slightly induced and IL-18 was not induced at the transcriptional level (Fig. 2a). Several chemokines (macrophage inflammatory protein-1 alpha (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1)) and cytokines (IL-6 and TNF) were taken along as a positive control for the inflammatory response, and all transcripts were markedly increased (Fig. 2b).Fig. 2


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)

Induction profile of immune mediators upon acute injury of the sciatic nerve. a Induction of IL-1 family members upon injury of the sciatic nerve, as shown by RT-qPCR analysis. b Induction of chemokines (MIP-1α and MCP-1) and cytokines (IL-6 and TNF) at different time points upon injury of the sciatic nerve. Data is analyzed using the ΔΔCt method, and mRNA expression levels are expressed relative to the basal condition (0-h time point). The graphs show the pooled data of five independent experiments (mean ± SD)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Induction profile of immune mediators upon acute injury of the sciatic nerve. a Induction of IL-1 family members upon injury of the sciatic nerve, as shown by RT-qPCR analysis. b Induction of chemokines (MIP-1α and MCP-1) and cytokines (IL-6 and TNF) at different time points upon injury of the sciatic nerve. Data is analyzed using the ΔΔCt method, and mRNA expression levels are expressed relative to the basal condition (0-h time point). The graphs show the pooled data of five independent experiments (mean ± SD)
Mentions: Next, we addressed whether Nlrs are regulated in the peripheral nerve upon inflammation. Sterile injury was induced by axotomy of the sciatic nerve. At different time points after the injury, the distal segment of the sciatic nerve was isolated; total RNA was isolated, converted to cDNA, and analyzed by RT-qPCR. The contralateral side was used as a control. We first analyzed the transcriptional regulation of the most established members of the IL-1 superfamily: IL-1α, IL-1β, IL-18, and IL-1 receptor antagonist (IL-1ra). Both IL-1β and the antagonist were highly induced already 4 h after injury (Fig. 2a). IL-1α was only slightly induced and IL-18 was not induced at the transcriptional level (Fig. 2a). Several chemokines (macrophage inflammatory protein-1 alpha (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1)) and cytokines (IL-6 and TNF) were taken along as a positive control for the inflammatory response, and all transcripts were markedly increased (Fig. 2b).Fig. 2

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