Emergency Myelopoiesis in Murine Arthritis Results in Cell-Intrinsic Changes in Dendritic Cell Development and Function

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects up to 0.5-1% of the adult global population.. Immune and inflammatory tissue damage is the main pathogenic mechanism in RA, and involves a hyperactivation of both innate and adaptive immune systems. Trained immunity, an important feature of the innate immune system, allows the host to mount functionally altered immune responses based on their previous history of immune exposures, independently of the classical adaptive immunological memory. However, the role of trained immunity in systemic autoimmune and inflammatory disorders remains poorly understood, with the effects on monocyte and macrophage differentiation and function being most widely studied. We demonstrate that emergency myelopoiesis is induced in chronic rheumatoid arthritis in murine models and acts not only to enhance the counts but also to produce functionally altered innate immune cells. Such effects are cell-intrinsic affecting hematopoietic stem and progenitor cells (HSPCs) and persist independently of the inflammatory disease milieu. Importantly, these trained immunity mechanisms impact not only macrophages but also dendritic cells, which are the major professional antigen presenting cells, bridging the innate and adaptive immune responses. Such mechanisms result in changes in the global transcriptional profiles of dendritic cells, and significantly alter their responses to recall immune stimulation and capacity for T cell activation. This study therefore represents the first demonstration of ‘dendritic cell trained immunity’ in rheumatoid arthritis.