ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Cell Metab. 2019 4;29:1363–1375.

Mesenchymal stem and/or stromal cells (MSCs) regulate immune system and have been associated with inflammatory and autoimmune diseases. The IGF system is mainly known for its role in the regulation of growth, development and metabolism. A possible role of IGF-I in inflammation has recently been proposed [1, 2], whereas the effects of IGF-II are largely unknown.

This elegant study investigated the IGF-II anti-inflammatory actions in a laboratory model of autoimmune encephalomyelitis (EAE). The authors demonstrated that: (A) human MSCs exposed to low oxygen (LO-MSCs) have anti-inflammatory effects secondary to the expression and production of IGF-II. The concentrated cell culture supernatant of MSCs was administered to EAE mice and was able to lower the EAE disease scores and improve the spinal cord histological appearance. (B) IGF-II administration to EAE significantly lowered the EAE clinical scores, decreased demyelination, and reduced mononuclear cell infiltration in the CNS. (C) IGF-II was found to act on maturing macrophages by programming them towards persistent oxidative phosphorylation (OXPHOS), which was not reduced by pro-inflammatory stimulation. This trained immune phenotype in macrophages imprinted by IGF-II was associated with reduced IL-1ß production and upregulated expression of PD-L1, a well-known immunosuppressive molecule. (D) The administration of IGF-II-preprogrammed macrophages to EAE mice increased Tregs and alleviated the disease in a PD-L1 dependent way. Metabolomic and epigenomic analyses showed that IGF-II-preprogrammed macrophages underwent both epigenetic and metabolic reprogramming, strongly supporting the notion that IGF-II is able to modulate the innate immune memory of macrophages.

Overall these results reveal an unexpected and novel action of IGF-II which, by training an important component of innate immune system toward an anti-inflammatory profile, may be beneficial in the context of autoimmune diseases.

References: 1. Hribal ML, Procopio T, Petta S, Sciacqua A, Grimaudo S, Pipitone RM, Perticone F, Sesti G. Insulin-like growth factor-I, inflammatory proteins, and fibrosis in subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2013;98:E304–308.

2. Bekkering S, Arts RJW, Novakovic B, Kourtzelis I, van der Heijden C, Li Y, Popa CD, Ter Horst R, van Tuijl J, Netea-Maier RT, van de Veerdonk FL, Chavakis T, Joosten LAB, van der Meer JWM, Stunnenberg H, Riksen NP, Netea MG. Metabolic Induction of Trained Immunity through the Mevalonate Pathway. Cell 2018;172:135–146.e139.