Immune dysfunction in developmental programming of type 2 diabetes mellitus

Abstract

Intrauterine growth restriction (IUGR) is a common complication of pregnancy and increases the risk of the offspring developing type 2 diabetes mellitus (T2DM) later in life. Alterations in the immune system are implicated in the pathogenesis of IUGR-induced T2DM. The development of the fetal immune system is a delicate balance as it must remain tolerant of maternal antigens whilst also preparing for the post-birth environment. In addition, the fetal immune system is susceptible to an altered intrauterine milieu caused by maternal and placental inflammatory mediators or secondary to nutrient and oxygen deprivation. Pancreatic-resident macrophages populate the pancreas during fetal development, and their phenotype is dynamic through the neonatal period. Furthermore, macrophages in the islets are instrumental in islet development as they influence β-cell proliferation and islet neogenesis. In addition, cytokines, derived from β-cells and macrophages, are important to islet homeostasis in the fetus and adult and, when perturbed, can cause islet dysfunction. Several activated immune pathways have been identified in the islets of people who experienced IUGR, with alternations in the levels of IL-1β and IL-4 as well as changes in TGFβ signalling. Leptin levels are also altered. Immunomodulation has shown therapeutic benefit in T2DM and might be particularly useful in IUGR-induced T2DM.

Fig. 1 |. Fetal immune development.

During a normal pregnancy, the fetus is exposed to maternal antigens, with the potential to elicit an immune response. To prevent inappropriate inflammation, the fetal immune system promotes tolerance of foreign antigens. At birth, the neonate is exposed to the environment and potential pathogens. In the neonate, the immune system shifts towards a pro-inflammatory phenotype. During these developmental windows, the phenotypes are determined by the dominant immune cell populations.

Fig. 2 |. Pancreatic immune development.

Macrophages populate the pancreas during embryogenesis, and their phenotype continues to develop during the perinatal period. Macrophages are influenced by their environment and adopt different phenotypes in the endocrine (that is, islets) compared with the exocrine tissue.

Fig. 3 |. Macrophages influence islet development.

Macrophages are instrumental to the maturation of pancreatic islets. a | In the adult, macrophages populate the islets and exocrine pancreas. b | In mice lacking macrophage colony-stimulating factor, there is a reduction of macrophages in the islets and of CD206⁺ macrophages in the exocrine pancreas. Islets of these mice are also smaller in size than those of wild-type mice, though more numerous.

Fig. 4 |. Resident macrophages sense their micro and systemic environments.

Islet-resident macrophages respond to intra-islet and systemic signals such as adipokines and cytokines (inflammatory signals). They in turn release cytokines (such as TGFβ and IL-1β) that influence β-cell function. These dynamic interactions are crucial to islet function and have the potential to cause pathology.

Fig. 5 |. Pancreatic inflammation subsequent to IUGR.

Intrauterine growth restriction (IUGR) alters islet macrophage populations and inflammatory signals. Offspring affected by IUGR have elevated M2-driven inflammation, altered TGFβ signalling and increased levels of IL-1β in fetal and neonatal islets. Islets isolated from adults who were affected by IUGR have elevated levels of IL-1β and leptin.