Somatic mutation in human macrophages: defining ontogeny and mechanisms of inflammatory disease

Macrophages—immune cells that defend, regulate, and repair tissues—can acquire mutations as they divide, and those mutations may drive inflammatory diseases that currently have no known cause. The problem is that scientists do not fully understand where different types of macrophages come from or how they renew. Some arise from primitive cells in the embryo and self-renew locally; others depend on a steady supply of monocytes from the bone marrow. This project will use naturally occurring “silent” mutations as genetic barcodes to trace each macrophage’s origin in human tissues. It will also examine macrophages carrying mutations from clonal haematopoiesis—a common, age-related condition in which blood stem cells acquire mutations—to see whether those altered macrophages accelerate diseases such as atherosclerosis. Finally, the team will search for clonal macrophage mutations in patients with idiopathic inflammatory disorders—IgG4-related disease, granulomatosis with polyangiitis, and sarcoidosis—that overlap with histiocytosis, a class of inflammatory myeloid cancers. If successful, this work could reveal that some chronic inflammatory diseases are actually driven by mutant macrophage clones, opening the door to targeted therapies. It may also clarify why certain tissues are vulnerable to inflammation with age. The research is fundamental science: it aims to map the hidden life history of human macrophages, with no immediate clinical application, but the same approach—using somatic mutations as a natural lineage tracer—has already transformed understanding of cancer evolution.