Theresa M Raimondo1,2, David J Mooney3,2. 1. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA. 2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. 3. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA. mooneyd@seas.harvard.edu.
Abstract
Chronic inflammation contributes to the pathogenesis of all muscular dystrophies. Inflammatory T cells damage muscle, while regulatory T cells (Tregs) promote regeneration. We hypothesized that providing anti-inflammatory cytokines in dystrophic muscle would promote proregenerative immune phenotypes and improve function. Primary T cells from dystrophic (mdx) mice responded appropriately to inflammatory or suppressive cytokines. Subsequently, interleukin-4 (IL-4)- or IL-10-conjugated gold nanoparticles (PA4, PA10) were injected into chronically injured, aged, mdx muscle. PA4 and PA10 increased T cell recruitment, with PA4 doubling CD4+/CD8- T cells versus controls. Further, 50% of CD4+/CD8- T cells were immunosuppressive Tregs following PA4, versus 20% in controls. Concomitant with Treg recruitment, muscles exhibited increased fiber area and fourfold increases in contraction force and velocity versus controls. The ability of PA4 to shift immune responses, and improve dystrophic muscle function, suggests that immunomodulatory treatment may benefit many genetically diverse muscular dystrophies, all of which share inflammatory pathology.
Chronic inflammation contributes to the pathogenesis of all muscular dystrophies. Inflammatory T cells damage muscle, while regulatory T cells (Tregs) promote regeneration. We hypothesized that providing anti-inflammatory cytokines in dystrophic muscle would promote proregenerative immune phenotypes and improve function. Primary T cells from dystrophic (mdx) mice responded appropriately to inflammatory or suppressive cytokines. Subsequently, interleukin-4 (IL-4)- or IL-10-conjugated gold nanoparticles (PA4, PA10) were injected into chronically injured, aged, mdx muscle. PA4 and PA10 increased T cell recruitment, with PA4 doubling CD4+/CD8- T cells versus controls. Further, 50% of CD4+/CD8- T cells were immunosuppressive Tregs following PA4, versus 20% in controls. Concomitant with Treg recruitment, muscles exhibited increased fiber area and fourfold increases in contraction force and velocity versus controls. The ability of PA4 to shift immune responses, and improve dystrophic muscle function, suggests that immunomodulatory treatment may benefit many genetically diverse muscular dystrophies, all of which share inflammatory pathology.
Authors: Mary L Vallecillo-Zúniga; Peter Daniel Poulson; Jacob S Luddington; Christian J Arnold; Matthew Rathgeber; Braden C Kartchner; Spencer Hayes; Hailie Gill; Jonard C Valdoz; Jonathan L Spallino; Seth Garfield; Ethan L Dodson; Connie M Arthur; Sean R Stowell; Pam M Van Ry Journal: Cells Date: 2021-11-17 Impact factor: 6.600