INTERLEUKIN-1 RESTRICTS HSC PROLIFERATION VIA A PU.1-DEPENDENT MECHANISM

Abstract

Chronic inflammation is often associated with myeloid overproduction that can contribute to the pathogenesis of a range of inflammatory diseases. Paradoxically, despite ongoing inflammatory signaling, depletion of the HSC compartment is rarely observed in inflammatory disease, suggesting the existence of mechanism(s) that prevent spurious HSC activation during chronic stress. However, the regulation of HSC during chronic inflammation is not well understood. To address this question, we are using a chronic, systemic interleukin-1 (IL-1) exposure that models the systemic inflammatory features of a range of human diseases. Strikingly, following 20 days of IL-1 treatment, HSC remain in a largely quiescent state accompanied by repression of protein synthesis, cell metabolism and proliferation genes including Myc. IL-1 exposed HSC also fail to proliferate in response to concurrent stress such as poly I:C. Along these lines, in vivo lineage tracing shows that HSC contributions to the blood system are not substantially different than at steady state, consistent with a largely dormant HSC pool during chronic inflammation. Mechanistically, maximal induction of the growth arrest program requires cell-autonomous IL-1R expression and is selectively induced in HSC with increased expression of the myeloid transcription factor PU.1. Notably, IL-1 treatment of PU.1KI/KI mice, which express ∼30% of normal PU.1 levels in HSC, leads to aberrant HSC expansion and cell cycle activity, indicating PU.1 acts as a ‘brake’ to prevent excess HSC proliferation. Altogether, our data identify a key circuit that suppresses HSC activity during chronic inflammation. They suggest inflammation-induced PU.1 may play a ‘positive’ role in HSC maintenance during chronic inflammation by preventing HSC exhaustion and/or expansion while limiting overproduction of potentially pathogenic blood cells.