Poster #060, Cedars Sinai Medical Center
Type I interferon priming during monopoiesis programs enhanced antiviral responsiveness in a subset of monocytes and macrophages
Mentors: Karina Nance, BS and Helen Goodridge, PhD
Macrophages are innate immune cells that can adopt diverse functional states during homeostasis, infection, and inflammation. While these states are often attributed to signals received after differentiation, our work asks whether macrophage heterogeneity is pre-programmed during their development from monocytes and progenitors. Previous findings from our lab showed that steady-state type I interferon signaling maintains a baseline antiviral program in bone marrow-derived macrophages, particularly in macrophages that arise from monocyte dendritic cell progenitors (MDPs). This program was associated with increased expression of interferon-stimulated genes, and stronger responses to poly(I:C) than macrophages derived from granulocyte-monocyte progenitors (GMPs). Single-cell RNA-seq of bone marrow Ly6Chi classical monocytes identified an interferon-high monocyte subset (IFMo) that is enriched for antiviral interferon-stimulated genes (ISGs) and arises from MDPs. This subset is dependent on steady-state type I interferon signaling and can be identified using an Mx1-GFP ISRE reporter mouse, in which Mx1-GFP high classical monocytes correspond to IFMo and Mx1-GFP low classical monocytes represent Non-IFMo. Based on these findings, we hypothesize that IFMo are pre-primed with interferon activity that is maintained after differentiation into macrophages, generating IFMo-derived macrophages (IFMacs) that respond faster to dsRNA than macrophages derived from Non-IFMo (Non-IFMacs). To test this, Mx1-GFP high IFMo and Mx1-GFP low Non-IFMo classical monocytes were sorted and cultured with M-CSF for four days to generate IFMacs and Non-IFMacs. After differentiation, macrophages were left unstimulated or stimulated with Poly(I:C) for 18 hours. Responses were assessed by flow cytometry for CD40, CD69, and CD86 activation marker expression and by Incucyte imaging to measure Mx1-GFP expression over time. Here, we show that IFMacs induce Mx1-GFP faster after Poly(I:C) stimulation, suggesting that steady-state type I interferon signaling imprints an antiviral program during monocyte development.