The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells

Abstract

SummaryInflammation triggers the differentiation of Ly6Chi monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3+CD11c−MHCII+PU.1hi subset. This subset acted as a precursor for FcγRIII+PD-L2+CD209a+, GM-CSF-dependent moDCs but was distal from the DC lineage, as shown by fate-mapping experiments using Zbtb46. By contrast, Flt3−CD11c−MHCII−PU.1lo monocytes differentiated into FcγRIII+PD-L2−CD209a−iNOS+ macrophages upon microbial stimulation. Importantly, Sfpi1 haploinsufficiency genetically distinguished the precursor activities of monocytes toward moDCs or microbicidal macrophages. Indeed, Sfpi1+/− mice had reduced Flt3+CD11c−MHCII+ monocytes and GM-CSF-dependent FcγRIII+PD-L2+CD209a+ moDCs but generated iNOS+ macrophages more efficiently. Therefore, intercellular disparities of PU.1 expression within naive monocytes segregate progenitor activity for inflammatory iNOS+ macrophages or moDCs.

Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes

“…In addition to the “neutrophil-like” monocytes, we also detected a smaller, separate subset of Ly6C hi monocytes expressing Cd209a , H2-Ab1 , H2-Aa and Flt3 (Figure S7G), which corresponded to the recently described moDC-producing monocytes (Menezes et al, 2016). Importantly, expression of the cDC transcription factor Zbtb46 was not detected in any of the Ly6C hi monocytes (Figure S7G).…”

“…A recent report demonstrated that moDCs originate from a subset of Ly6C hi monocytes expressing the genes encoding MHCII, Flt3 and CD209a (Menezes et al, 2016). Consistent with this, we observed much stronger expression of these genes by MDP-derived Ly6C hi monocytes than their GMP-derived counterparts (Figure 5J).…”

“…Two major types of monocytes have been reported in mice and humans (Geissmann et al, 2003; Passlick et al, 1989), although single-cell transcriptome profiling studies have recently revealed additional heterogeneity (Menezes et al, 2016; Villani et al, 2017). In mice, the most notable distinction is between classical or inflammatory monocytes, which strongly express Ly6C, and non-classical monocytes (including patrolling monocytes), which lack Ly6C (Carlin et al, 2013; Geissmann et al, 2003; Zhu et al, 2016).…”

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…Nevertheless, Ly6C hi monocytic cells have the potential to differentiate into several subsets with antigen-presenting and cross-presenting capacity. 33 This requires upregulation of peptide-presenting MHC class II and class I molecules as well as enhanced expression of co-stimulatory signals, including CD80, CD86, and CD40, which are necessary for proper T cell activation via CD28 and CD40L. 34 Along these lines, it becomes increasingly evident that monocytic cells can give rise to a population of monocytic APCs which are of importance for the stimulation of anti-tumor immune mechanisms during cancer therapy – at least in mouse tumor models.…”

The immune cell landscape in kidneys of lupus nephritis patients

“…During tissue injury, monocytes can enter tissues from the peripheral blood and can further differentiate into inflammatory macrophages and reparative/resolving macrophages in situ 55,56,57 . If the cells are chronically exposed to damage-associated molecular pattern molecules (DAMPs) and endosomal TLR ligands, resolution may fail, and macrophages with mixed functions may emerge 58 .…”