NLRP2 Is Overexpressed in Spinal Astrocytes at the Peak of Mechanical Pain Sensitivity during Complete Freund Adjuvant-Induced Persistent Pain.

László Ducza,Krisztina Hegedűs,Andrea Gajtkó,Erzsébet Bakk,Ildikó Wéber,Krisztina Holló,Péter Szücs

doi:10.3390/ijms222111408

László Ducza, Krisztina Hegedűs + Show 5 more

Open Access

https://doi.org/10.3390/ijms222111408

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Abstract

Our earlier findings revealed that interleukin-1 receptor type-1 (IL-1R1) was overexpressed in spinal neurons, and IL-1R1-deficient mice showed significant attenuation of thermal and mechanical allodynia during the course of the Complete Freund adjuvant (CFA)-induced persistent pain model. In the present study, we found that a ligand of IL-1R1, termed interleukin-1β (IL-1β), is also significantly overexpressed at the peak of mechanical pain sensitivity in the CFA-evoked pain model. Analysis of cellular distribution and modeling using IMARIS software showed that in the lumbar spinal dorsal horn, IL-1β is significantly elevated by astrocytic expression. Maturation of IL-1β to its active form is facilitated by the formation of the multiprotein complex called inflammasome; thus, we tested the expression of NOD-like receptor proteins (NLRPs) in astrocytes. At the peak of mechanical allodynia, we found expression of the NLRP2 inflammasome sensor and its significantly elevated co-localization with the GFAP astrocytic marker, while NLRP3 was moderately present and NLRP1 showed total segregation from the astrocytic profiles. Our results indicate that peripheral CFA injection induces NLRP2 inflammasome and IL-1β expression in spinal astrocytes. The release of mature IL-1β can contribute to the maintenance of persistent pain by acting on its neuronally expressed receptor, which can lead to altered neuronal excitability.

Highlights

The treatment of chronic pain due to inflammatory diseases is a major problem in clinical practice
From the numerous molecules involved in neuron–glia bidirectional communication, in this study we focused on IL-1β, a pro-inflammatory cytokine which plays an essential role in host response to bacterial and viral infections [15,16,17], as it is involved in several inflammatory disorders leading to the development of chronic pain [18]
Our earlier findings support the importance of the IL-1 signaling pathway in chronic pain: we found significant attenuation of both mechanical and thermal allodynia in interleukin-1 receptor type-1 (IL-1R1)-deficient mice during the course of Complete Freund adjuvant (CFA)-evoked persistent pain [28]

Summary

Introduction

The treatment of chronic pain due to inflammatory diseases is a major problem in clinical practice. Pathological pain can be caused by peripheral tissue injury followed by inflammation or nerve injury. Peripheral tissue or nerve injuries and inflammation evoke long-lasting changes in nociceptive-processing microcircuits [2,3,4,5,6]. It is increasingly accepted that glial cells, glia activated via neuronal stimulation, are able to modulate neuronal excitability; in this way, they can influence the plastic changes during pathological pain conditions [7,8,9]. Of the huge variety of substances released by activated glial cells, pro-inflammatory cytokines (e.g., interleukin-1β/IL-1β/, tumor necrosis factor-α/TNF-α/, interleukin-6/IL-6/) appear to be of special importance in the creation of neuronal hyperexcitability [14]

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