Fibroblast-Derived PI16 Sustains Inflammatory Pain via Regulation of CD206+ Myeloid Cells

Authors

Rachelle Garrity
Neha Arora
Md Areeful Haque
Drew Weis
Ronnie T Trinh
Sanjay V Neerukonda
Susmita Kumari
Ibdanelo Cortez
Eroboghene E Ubogu
Rajasekaran Mahalingam
Diana Tavares-Ferreira
Theodore J Price
Annemieke Kavelaars
Cobi J Heijnen
Andrew J Shepherd

Publication Date

8-1-2023

Journal

Brain, Behavior, and Immunity

Abstract

Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund’s Adjuvant inflammatory pain model, we show that Pi16-/- mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain. In contrast to neuropathic pain models, we did not observe any changes in blood-nerve barrier permeability due to PI16 deletion. Instead, Pi16-/- mice display reduced macrophage density in the CFA-injected hindpaw. Furthermore, there was a significant bias toward CD206hi (anti-inflammatory) macrophages in the hindpaw and associated dorsal root ganglia. Following CFA, intrathecal depletion of CD206+ macrophages using mannosylated clodronate liposomes promoted sustained pain in Pi16-/- mice. Similarly, an IL-10 neutralizing antibody also promoted sustained CFA pain in the Pi16-/ when administered intrathecally. Collectively, our results point to fibroblast-derived PI16 mediating substantial differences in macrophage phenotype in the pain neuroaxis under conditions of inflammation. The co-expression of PI16 alongside fibroblast markers in human DRG raise the likelihood that a similar mechanism operates in human inflammatory pain states. Collectively, our findings may have implications for targeting fibroblast-immune cell crosstalk for the treatment of chronic pain.

Keywords

Mice, Humans, Animals, Chronic Pain, Neuralgia, Inflammation, Macrophages, Fibroblasts, Antibodies, Neutralizing, Ganglia, Spinal, Hyperalgesia, Carrier Proteins, Glycoproteins, PI16, Complete Freund’s Adjuvant, pain, inflammation, fibroblast, macrophage, blood-nerve barrier, meninges, CD206, IL-10

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Associated Data

PMID: 37315702