Bone marrow suppression and pancytopenia can result from chronic inflammation. Bone marrow suppression is a risk factor for increased mortality for patients with chronic infections14-17 and aplastic anemia18-21. However, very little is known about the mechanisms by which inflammatory cytokines affect the hematopoietic progenitors that reside in bone marrow.
We discovered that interferon gamma (IFNγ) promotes hematopoietic stem cell (HSC) division and myeloid differentiation in a mouse model of Mycobacterium avium infection1. While this response can be helpful in the short term, it may be deleterious over the long term, with prolonged inflammation leading to stem cell exhaustion2.
We have previously demonstrated that interferons, a class of inflammatory cytokines, directly activate hematopoietic stem cells (HSCs) to divide (Nature 2010). HSCs are the precursors of all cells of the peripheral blood, and they usually reside in a quiescent state in the bone marrow.
Our work is among the first to demonstrate that inflammatory signaling can directly activate HSCs. Impaired quiescence mechanisms during long-term interferon stimulation result in differentiation and exhaustion of the HSC pool (Blood 2011, Stem Cells 2014). We recently demonstrated that chronic infection depletes HSCs through excessive terminal differentiation, in part mediated by the transcription factor Batf2 (Cell Reports 2016). Meanwhile, basal inflammatory signaling mediated through the intestinal microbiome is required to maintain normal blood homeostasis (Blood, 2017).
Ongoing work is focused on defining molecular pathways underlying these phenomena. This knowledge is a key to understanding the pathophysiology of bone marrow failure syndromes and will likely provide novel targets for drug development. Furthermore, this work may elucidate how inflammatory signals affect the pattern of HSC differentiation as well as how infections can contribute to aging and oncogenesis.
See a list and descriptions of our current projects.
- Scientists find persistent infections in mice exhaust progenitors of all blood cells; potential treatment possibleDec 6, 2016
- Mouse model reveal that long-lasting infections trigger the loss of progenitors of blood cells and suggest a strategy that may help prevent or treat this condition in the future.