I am a
Home I AM A Search Login

Papers of the Week

Papers: 10 Jun 2023 - 16 Jun 2023

Basic Science

Animal Studies, Molecular/Cellular, Neurobiology

Inflammation/Inflammatory, Psychological/Comorbidities

2023 Jun 12

Brain Behav Immun


Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206 myeloid cells.


Garrity R, Arora N, Areeful Haque M, Weis D, Trinh RT, Neerukonda SV, Kumari S, Cortez I, Ubogu EE, Mahalingam R, Tavares-Ferreira D, Price TJ, Kavelaars A, Heijnen CJ, Shepherd AJ


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 CD206 (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 and macrophage 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.