Enhanced Medullary and Extramedullary Granulopoiesis Sustain the Inflammatory Response in Lupus Nephritis

Abstract

Abstract In order to meet the increased demand for effector cells in the periphery, systemic inflammation promotes medullary and extramedullary myelopoiesis. Extramedullary hematopoiesis (EMH) is emerging as a key player for tissue injury in systemic autoimmune disorders. In Systemic Lupus Erythematosus (SLE), deregulation of hematopoiesis is characterized by myeloid skewing and trained immunity with priming of proinflammatory ‘immune trained’-hematopoietic stem and progenitor cells (HSPCs). Here, by the use of the NZBW/F1 lupus-prone model we demonstrate that in diseased mice, splenic EMH is enhanced and skewed towards myeloid cell production correlating with lupus nephritis (LN) activity. Transcriptomic analysis shows that splenic HSPC carry a higher inflammatory potential compared to their bone marrow (BM) counterparts. Further induction of trained immunity, through β-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsenes LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which in part is driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice. Our results suggest that both EMH and trained immunity contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare.