Insulin-like growth factor-1 receptor controls the function of CNS-resident macrophages and their contribution to neuroinflammation

• Published in: Acta neuropathologica communications 2023-03, Vol.11 (1), p.35-35, Article 35
• Main Authors: Ivan, Daniela C, Berve, Kristina Carolin, Walthert, Sabrina, Monaco, Gianni, Borst, Katharina, Bouillet, Elisa, Ferreira, Filipa, Lee, Henry, Steudler, Jasmin, Buch, Thorsten, Prinz, Marco, Engelhardt, Britta, Locatelli, Giuseppe
• Format: Article
• Language: English
• Subjects: Animals; Border associated macrophages; Central Nervous System - metabolism; Central Nervous System - pathology; Disease; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Ethylenediaminetetraacetic acid; Experimental autoimmune encephalomyelitis; Health aspects; Homeostasis; IGF-1; IGF-1R; Inflammation; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Macrophages; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Multiple sclerosis; Multiple Sclerosis - pathology; Neuroinflammatory Diseases; Polymerase chain reaction; RNA; RNA sequencing; Spinal cord
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-023-01535-8

Signaling by insulin-like growth factor-1 (IGF-1) is essential for the development of the central nervous system (CNS) and regulates neuronal survival and myelination in the adult CNS. In neuroinflammatory conditions including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), IGF-1 can regulate cellular survival and activation in a context-dependent and cell-specific manner. Notwithstanding its importance, the functional outcome of IGF-1 signaling in microglia/macrophages, which maintain CNS homeostasis and regulate neuroinflammation, remains undefined. As a result, contradictory reports on the disease-ameliorating efficacy of IGF-1 are difficult to interpret, together precluding its potential use as a therapeutic agent. To fill this gap, we here investigated the role of IGF-1 signaling in CNS-resident microglia and border associated macrophages (BAMs) by conditional genetic deletion of the receptor Igf1r in these cell types. Using a series of techniques including histology, bulk RNA sequencing, flow cytometry and intravital imaging, we show that absence of IGF-1R significantly impacted the morphology of both BAMs and microglia. RNA analysis revealed minor changes in microglia. In BAMs however, we detected an upregulation of functional pathways associated with cellular activation and a decreased expression of adhesion molecules. Notably, genetic deletion of Igf1r from CNS-resident macrophages led to a significant weight gain in mice, suggesting that absence of IGF-1R from CNS-resident myeloid cells indirectly impacts the somatotropic axis. Lastly, we observed a more severe EAE disease course upon Igf1r genetic ablation, thus highlighting an important immunomodulatory role of this signaling pathway in BAMs/microglia. Taken together, our work shows that IGF-1R signaling in CNS-resident macrophages regulates the morphology and transcriptome of these cells while significantly decreasing the severity of autoimmune CNS inflammation.