On macrophage contributions to tissue homeostasis : New insights on pancreas development and healing of ischemic injury

Sammanfattning: Besides providing host defence against innumerable threats, macrophages display additional key functions for preservation of tissue homeostasis. This thesis includes four studies that explore novel macrophage functions in both the development of islets of Langerhans and healing of ischemic injury in mice.The aim of Study I was to explore the involvement of pancreatic macrophages in postnatal islet development. We found that neonatal pancreas contained high density of macrophages. Neonatal infections reduced the number of pancreatic macrophages transiently and resulted in both impaired β cell maturation and associated long-standing glucose intolerance. Moreover, clodronate depletion of pancreatic macrophages in the neonate also resulted in long-standing impairment of glucose handling. Together, these results demonstrate that macrophages in the neonatal pancreas are important for maturation of islet function.We then wanted to understand how macrophages contribute to healing of ischemic injury based on the observation that they accumulate at perivascular positions following ischemia. We found that blood flow at the site of ischemia was regulated by perivascular macrophages in an iNOS-dependent manner, which could be targeted to increase tissue healing (Study II). Next, we investigated if these perivascular macrophages trans-differentiate into mural cells. By lineage tracing, we found that macrophages undergo a phenotype shift at the site of ischemic injury, as they down-regulated the expression of myeloid cell lineage markers (CD45/CX3CR1/CD11b) and upregulated the expression of the mural cell marker PDGFRβ (Study III). Lastly, we addressed if macrophages are involved in vascular remodelling important for tissue normalization by pruning excessive vessels at the site of injury. Indeed, MMR+-macrophages were found to support vessel pruning during vascular normalization at late phases of healing (Study IV).In conclusion, this thesis reveals novel functions of macrophages as they support postnatal maturation of the insulin-producing β cells of the pancreas, as well as restore blood flow and normalize the vasculature during healing of ischemic injuries. Together, the studies in this thesis contribute to illustrating the ample and diverse macrophage curriculum and how macrophage skills cooperate to ensure homeostasis.