RATIONALE: Until now, the effect of IL-17A on hematopoiesis has been attributed to an indirect loop through non-hematopoietic cells (i.e. stroma cells) stimulating secretion of hematopoietic factors such as GM-CSF and IL-6. However, we hypothesized that IL-17A can directly signal to hematopoietic stem and progenitor cells (HSPCs) to determine their expansion and differentiation.
METHODOLOGY: We analyzed the expression of IL-17-signaling pathway in publicly available hematopoietic single-cell RNAseq datasets. For isolation of HSPCs we used FACS. Spectral flow cytometry and confocal microscopy were used for analysing IL-17RA/ACT-1 expression and differentiation of HSPCs as well as IL-17-producing cells in bone marrow.
RESULTS: IL-17-signaling pathway is up-regulated in human and mouse HSPCs, accompanied by enrichment in the human hematopoietic stem cell inflammatory memory compartment. IL-17A supplementation leads to an increase in clonogenic capacity of mouse HSPC, with increment in the monocyte-granulocyte potential. In liquid culture, supplementation with IL-17A leads to a greater expansion of sorted HSPCs through MPP3/MPP4 expansion, accompanied by an increased proportion of myeloid-monocyte committed cells. IL-17A is detectable in bone marrow, with possible production from subsets of RORγt+ and non- RORγt+ cells.