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

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.

Enhanced nociceptive behavior and expansion of associated primary afferents in a rabbit model of cerebral palsy

“…Neuroinflammation and pain are tightly intertwined (Grace et al, 2014) and astrogliosis has a well-established role in other painful conditions. After complete spinal cord injury, increased GFAP persists for at least 3 weeks in the adult rat spinal cord (Choi et al, 2021;Ducza et al, 2021;Morin-Richaud et al, 1998;Nesic et al, 2006;Xu et al, 2021). However, the time course of the GFAP response to injury is different in neonates.…”

“…Astrocytes and microglia are activated by neural injury and release a plethora of pro-inflammatory molecules into the spinal milieu, and their activation corresponds to the development of neuropathic pain (Chhaya et al, 2018;Detloff et al, 2008;Gao et al, 2009;Hulsebosch et al, 2009;Ishikura et al, 2021;Lu et al, 2021;Xie et al, 2009;Zhang et al, 2016Zhang et al, , 2007. After complete spinal cord injury, increased GFAP persists for at least 3 weeks in the adult rat spinal cord (Choi et al, 2021;Ducza et al, 2021;Morin-Richaud et al, 1998;Nesic et al, 2006;Xu et al, 2021). However, the time course of the GFAP response to injury is different in neonates.…”

Mitochondria and sensory processing in inflammatory and neuropathic pain

“…For example, in the CFA-induced chronic inflammatory pain, the compound muscone, which diminishes ROS production, prevented the loss of mitochondrial membrane potential and Ca 2+ influx. Moreover, it blocked the CFA-induced increase in spinal cord NLRP3 and IL-1β expression and hyperalgesia (87,196). Importantly, the downstream product of inflammasome activation, IL-1β, induces firing of nociceptors and mediates CFA-induced pain (189,197,198), suggesting a putative role for NLRP3 inflammasome activation in inflammatory pain.…”

Glial Cells and Brain Diseases: Inflammasomes as Relevant Pathological Entities

“…It has been reported that pain-related clinical situations and experimental models are associated with inflammatory response activation in astrocytes ( Tan et al, 2021 ). Both NLRP2 and NLRP3 have been identified in spinal cord astrocytes during in situations of mechanical pain hypersensitivity in the complete Freund adjuvant-induced persistent pain model with IL-1β as effector and by activating the sphingosine-1-phosphate receptor ( Doyle et al, 2019 ; Ducza et al, 2021 ). It has been shown that the inflammatory activation in spinal cord astrocytes, and the associated pain, can be alleviated by treatment with the stilbenoid resveratrol ( Fan et al, 2021 ), and the molecular reduction of heat shock protein family A member 8 (HSPA8) ( Mi et al, 2021 ).…”