The role of STAT1 in infection-induced EMH

Extramedullary haematopoiesis (EMH) refers to the production of mature blood cells outside the bone marrow. It occurs during foetal development and under pathological stress in adults, such as bone marrow failure, infection/inflammation or in myeloproliferative diseases. During infectious and inflammatory diseases, EMH is an important mechanism to compensate for an increased immune cell demand, in particular when bone marrow haematopoiesis is disrupted. EMH typically occurs in vascular tissues, most frequently in the spleen. It requires the reactivation or establishment of a specialized microenvironment (haematopoietic niche) that enables the attraction, proliferation and differentiation of haematopoietic stem and progenitor cells (HSPCs). Despite the growing understanding of demand-adapted haematopoiesis in the bone marrow, the molecular mechanisms that regulate splenic EMH are poorly understood. We have recently discovered that signal transducer and activator of transcription (STAT) 1 in myeloid cells (i.e. monocytes, macrophages and neutrophils) has an important role in the induction of splenic EMH during murine cytomegalovirus (MCMV) infection. We are now investigating the mechanisms and identifying the myeloid cell type that drives EMH through STAT1. We are using mice with conditional deletion of STAT1 in tissue-resident macrophages, cutting-edge next generation sequencing, proteomics and imaging approaches coupled with adoptive transfer and tracking experiments to characterize cellular and signalling networks that direct splenic EMH in response to MCMV infection. Our study will significantly advance the understanding of the innate immune response of splenic macrophages and their cross-talk to the HSPC pool. It will also shed light on the heterogeneity and plasticity of splenic HSPCs and the extramedullary hematopoietic response to viral infection.