STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia

Giulio Morozzi; Julian Rothen; Gauthier Toussaint; Katrina De Lange; Katrin Westritschnig; Arno Doelemeyer; Vanessa Pitiot Ueberschlag; Peter Kahle; Christian Lambert; Michael Obrecht; Nicolau Beckmann; Veronique Ritter; Moh Panesar; Daniela Stauffer; Isabelle Garnier; Matthias Mueller; Danilo Guerini; Caroline Gubser Keller; Judith Knehr; Guglielmo Roma; Michael Bidinosti; Sophie Brachat; Frederic Morvan; Mara Fornaro

doi:10.1016/j.isci.2021.103434

STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia

iScience. 2021 Nov 14;24(12):103434. doi: 10.1016/j.isci.2021.103434. eCollection 2021 Dec 17.

Authors

Giulio Morozzi¹, Julian Rothen¹, Gauthier Toussaint¹, Katrina De Lange², Katrin Westritschnig¹, Arno Doelemeyer¹, Vanessa Pitiot Ueberschlag¹, Peter Kahle¹, Christian Lambert¹, Michael Obrecht¹, Nicolau Beckmann¹, Veronique Ritter¹, Moh Panesar¹, Daniela Stauffer¹, Isabelle Garnier¹, Matthias Mueller², Danilo Guerini³, Caroline Gubser Keller², Judith Knehr², Guglielmo Roma², Michael Bidinosti¹, Sophie Brachat¹, Frederic Morvan¹, Mara Fornaro¹

Affiliations

¹ Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
² Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
³ Autoimmunity and Inflammation, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.

Abstract

Inflammatory responses are crucial for regeneration following peripheral nerve injury (PNI). PNI triggers inflammatory responses at the site of injury. The DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING) sense foreign and self-DNA and trigger type I interferon (IFN) immune responses. We demonstrate here that following PNI, the cGAS/STING pathway is upregulated in the sciatic nerve of naive rats and dysregulated in old rats. In a nerve crush mouse model where STING is knocked out, myelin content in sciatic nerve is increased resulting in accelerated functional axon recovery. STING KO mice have lower macrophage number in sciatic nerve and decreased microglia activation in spinal cord 1 week post injury. STING activation regulated processing of colony stimulating factor 1 receptor (CSF1R) and microglia survival in vitro. Taking together, these data highlight a previously unrecognized role of STING in the regulation of nerve regeneration.

Keywords: Cell biology; Immunology; Molecular biology; Neuroscience.