The role of CCL2/MCP-1 produced by peripheral sensory neurons in neuropathic pain

Author(s)

Atlante Silva Mendes

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-02-08

Examining board members

Thiago Mattar Cunha; Moises Evandro Bauer; Camila Squarzoni Dale; Sabrina Francesca de Souza Lisboa

• Advisor: Thiago Mattar Cunha

Abstract

Neuropathic pain involves changes in the characteristics of neurons that signal pain as well as along the entire neuro-axis. Persistent pain sensation and inflammation are shown in different clinical conditions and contribute to development of neuropathic pain. In this context, chemokines and their receptors are widely expressed by nonneuronal and neuronal cells and play a role in regulating immune cell migration. The CCL2/CCR2 pathway contributes to neuropathic pain in several models of nervous system injury. However, there are controversies regarding the cell type responsible for the release of CCL2 in the sensory microenvironment. Thus, this study aimed to evaluate the role of CCL2 in the neuropathic pain, with emphasis on peripheral sensory neurons. Validation of SNI model was performed by evaluating injury-related gene in DRG and spinal cord. CCL2 was evaluated in these tissues after injury over time. We validated the participation of CCL2 in SNI model by evaluating pain behavior in CCL2- deficient mice. CCL2 tissue expression was assessed by reanalysis of single cell sequencing databases of DRG and meninges from healthy mice and rats. We analyzed the role of sensory neurons in the production of CCL2 by conditional CCL2-depleted mice (Nav1.8+CCL2fl/fl). We evaluated CCL2 expression in other cell types, such as microglia and macrophages, by reanalysis of single cell sequencing databases in nerve crush and SNI models. The role of CCR2 was analyzed by evaluating pain behavior in CCR2-deficient mice. Leukocyte recruitment from meninges was assessed by confocal microscopy. The study was carried out with the approval of the Ethics Committee (05/2019). The results showed that there is alteration in the expression of different gene markers of neuronal injury and macrophage activation in DRG and spinal cord during SNI over time. Both CCL2 and CCR2 depletion decrease mechanical and thermal response. However, conditional depletion of CCL2 in neurons does not modify these responses. The analysis of different databases suggests an enrichment of CCL2 expression in resident macrophages from DRG, microglia and meningeal macrophages. Finally, It was shown recruitment of CCR2+ leukocytes to the meninges. Thus, we conclude that CCL2 seems to be produced by ganglionic macrophages and contributes to the infiltration of CCR2+ cells in the meninges. (AU)

• FAPESP's process: 18/24063-5 - Role of CCL-2/MCP-1 produced by peripheral sensorial neurons in the development of neuropathic pain
• Grantee: Atlante Silva Mendes
• Support Opportunities: Scholarships in Brazil - Doctorate