Balancing the Qi in ITP
James L. Zehnder · Blood · 2022
high expression of the IL-13 receptor α1 in megakaryocytes isolated from patients with MF compared with weak expression in megakaryocytes isolated from patients with essential thrombocythemia (ET) and polycythemia vera (PV).It is known that STAT6 signaling is activated downstream of the IL-13/IL-4 receptor and that this leads to the transcription of TGF-β.Concordant with this, they found increased level of phosphorylated STAT6 in megakaryocytes from both healthy donors and patients with MF following IL-13 stimulation (see figure).To assess the effect of modulating IL-13 signaling in fibrosis progression, the authors investigated both IL-13 overexpression and IL-4ra knockout in MPN mouse models.Jak2 V617F mice overexpressing IL-13 showed features of early bone marrow fibrosis with increased active TGF-β.Conversely, IL-4ra knockout reduced bone marrow fibrosis, decreased spleen weights in MPL W515L mice, and prolonged survival, findings with disease relevance for human MF.Last, Melo-Cardenas et al interrogated single-cell RNA-sequencing data from both prefibrotic and fibrotic bone marrow in both Jak2 V617F and MPL W515L mice and found that mast cells and T cells were increased at the fibrotic stage, with both being known sources of IL-13. 8 Concordant with this, bone marrow mast cells positive for TGF-β and IL-13 have been associated with higher fibrotic grade in human MF. 9 A limitation of the study is that although the authors confirmed mast cells as a key cellular source of IL-13 in their MPN mouse models, they were not able to test if eradicating mast cells reduced the fibrotic phenotype.If that were the case, this would make mast cells an attractive cellular target, as suggested by prior studies in human MF. 9