Interleukin-33 directly drives the expansion of myeloid cells and their progenitors in vivo

Respiratory diseases like COPD are characterized by uncontrolled inflammation that ultimately cause irreversible tissue damage and organ failure. Many studies reveal a role for granulocytes as key mediators of airway inflammation. The alarmins, IL-33,TSLP and IL-25, are epithelial derived cytokines that are regulated by environmental triggers to promote induction of key pathogenic cytokines. While their contribution to eosinophil biology is well-established, their effects on other myeloid derived populations is less understood. We found that of the three alarmins, IL-33 had the broadest effect in bone marrow cultures, and uniquely drove the expansion of all myeloid populations. Mechanistically, IL-33 induced production of myeloid lineage growth factors like GM-CSF. This effect was lost in ST2/IL-33 receptor-deficient or Myd88-deficient bone marrow. The IL-33 receptor, ST2, was detected on the earliest hematopoietic stem cells (HSC), Common Myeloid Progenitors (CMP) and Common Granulocyte Macrophage Progenitors (GMP). Culturing of sorted HSCs or progenitors with IL-33 dramatically enhanced their proliferation in a cell-intrinsic manner. Intranasal treatment of wildtype mice with IL-33 led to expansion of HSC, progenitor and all mature myeloid lineages in both the lung tissue and bone marrow. Furthermore administration of exogenous IL-33 promoted the rapid replenishment of circulating eosinophils and neutrophils in the cyclophosphamide model of myeloablation. Our studies identify a novel role for IL-33 in the expansion of myeloid cells and their precursors, and suggest that IL-33 could have a broad role promoting the immune cell mediated damage seen in respiratory disorders.