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.

How the spleen helps rebuild the blood and immune system during viral infection During severe infections and inflammation, the body must rapidly produce new blood and immune cells. While this normally occurs in the bone marrow, under these conditions blood cell production can temporarily shift to other organs, particularly the spleen, in a process known as extramedullary haematopoiesis. Our project investigated how the immune signalling protein STAT1 and the specialized cellular environment of the spleen regulates this emergency blood cell production during infection and inflammation. We combined murine cytomegalovirus and sterile inflammation models, together with advanced genetic, genomic, proteomic and imaging approaches, we mapped the splenic stem and progenitor cell populations and identified the cellular signals that activate this emergency programme. We discovered that both viral infection and sterile inflammation trigger a marked expansion of natural killer (NK) cell progenitors in the spleen. These progenitors develop into fully functional NK cells, whereas the bone marrow shows a reduced capacity to generate mature NK cells during infection. This finding demonstrates that EMH extends beyond the production of red blood cells and myeloid cells to include NK cells, establishing the spleen as an important reserve site for antiviral immunity when immune demand is high. In parallel, we identified a selective role for STAT1 signalling in macrophages in shaping splenic extramedullary haematopoiesis. STAT1 activity in these cells promotes the final stages of erythrocyte development and supports the maturation of platelet-producing cells from their committed progenitors, while constraining the generation of progenitors for other blood cell lineages. Ongoing work is identifying STAT1dependent myeloid cues that remodel the splenic niche and reprogram gene expression in hematopoietic stem and progenitor cells. Overall, our findings broaden the concept of extramedullary haematopoiesis by showing that the spleen acts as a flexible backup organ capable of tailoring blood and immune cell production to meet changing physiological demands. By identifying macrophage STAT1 as a key regulator of this process, our work provides new insight into how the body prioritises the production of different blood cell types during systemic inflammation. These discoveries could ultimately help guide new strategies to improve immune function and restore healthy blood cell production in patients with severe infections, bone marrow failure, inflammatory diseases and other conditions in which normal blood formation is impaired.