TY - JOUR
T1 - Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206+ myeloid cells
AU - Garrity, Rachelle
AU - Arora, Neha
AU - Haque, Md Areeful
AU - Weis, Drew
AU - Trinh, Ronnie T.
AU - Neerukonda, Sanjay V.
AU - Kumari, Susmita
AU - Cortez, Ibdanelo
AU - Ubogu, Eroboghene E.
AU - Mahalingam, Rajasekaran
AU - Tavares-Ferreira, Diana
AU - Price, Theodore J.
AU - Kavelaars, Annemieke
AU - Heijnen, Cobi J.
AU - Shepherd, Andrew J.
N1 - Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - Blood-nerve barrier
KW - CD206
KW - Complete Freund's Adjuvant
KW - Fibroblast
KW - IL-10
KW - Inflammation
KW - Macrophage
KW - Meninges
KW - Pain
KW - PI16
UR - http://www.scopus.com/inward/record.url?scp=85162986215&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85162986215&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2023.06.011
DO - 10.1016/j.bbi.2023.06.011
M3 - Article
C2 - 37315702
AN - SCOPUS:85162986215
SN - 0889-1591
VL - 112
SP - 220
EP - 234
JO - Brain, behavior, and immunity
JF - Brain, behavior, and immunity
ER -