IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms
Lukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène Wasmer, Regula Stuber, Alexandre P. Theocharides, Xiaohong Li, Yu Xia, Hirohisa Saito, Susumu Nakae, Gabriela M. Baerlocher, Markus G. Manz, Kathy D. McCoy, Andrew J. Macpherson, Adrian F. Ochsenbein, Bruce Beutler, Philippe Krebs
Lukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène Wasmer, Regula Stuber, Alexandre P. Theocharides, Xiaohong Li, Yu Xia, Hirohisa Saito, Susumu Nakae, Gabriela M. Baerlocher, Markus G. Manz, Kathy D. McCoy, Andrew J. Macpherson, Adrian F. Ochsenbein, Bruce Beutler, Philippe Krebs
View: Text | PDF
Research Article Hematology

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell–derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33–expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.

Authors

Lukas F. Mager, Carsten Riether, Christian M. Schürch, Yara Banz, Marie-Hélène Wasmer, Regula Stuber, Alexandre P. Theocharides, Xiaohong Li, Yu Xia, Hirohisa Saito, Susumu Nakae, Gabriela M. Baerlocher, Markus G. Manz, Kathy D. McCoy, Andrew J. Macpherson, Adrian F. Ochsenbein, Bruce Beutler, Philippe Krebs

×

Figure 4

ST2 expression and function in the BM.

Options: View larger image (or click on image) Download as PowerPoint
ST2 expression and function in the BM. (A) ST2 expression on hematopoiet...
(A) ST2 expression on hematopoietic BM cells is restricted to committed myeloid cells (CD11bint, Ly6G–, and Ly6C–). Representative histogram of one styx and one WT mouse is shown. (B) Cytospin of FACS-purified BM CD11bint, Ly6G–, Ly6C–, ST2+ cells showing phenotypical heterogeneity (scale bars: 20 μm). (C) ST2 expression on BM endothelial cells (defined as CD45–, lin–, CD51–, and CD31+). (D) Lin– BM cells from styx and WT mice were cultured in methylcellulose with the indicated cytokines. Colony numbers were assessed after 7 days. (E) BM primary stromal cells were grown in vitro (46). MACS-purified CD45– cells from these cultures were stimulated with IL-33 for 24 hours, before addition of lin– cells for coculture. Alternatively, lin– cells were supplemented with conditioned medium from FACS-purified CD11bint, Ly6G–, and Ly6C– cells previously stimulated with IL-33 for 24 hours. Then, styx St2–/– or St2–/– lin– cells incubated for 48 hours under these respective conditions were cultured in methylcellulose for 7 days, and colony formation was assessed. Conditions for culture (± IL-33) and genotypes of stromal or hematopoietic stimulation responders (+: styx St2+/+; -: styx St2–/–) are indicated. Data are mean ± SEM and are representative of (A) n = 8 mice per group; (B) n = 2 mice per group; (C) pooled cells from 4 WT mice, repeated twice; (D) pooled data of 2 experiments, n = 6 mice per group; and (E) 1 experiment where each data point represents 2 pooled mice (n = 6 mice per group). Stromal and hematopoietic responders were pooled from 5 donors. (D and E) One-way ANOVA with Bonferroni post hoc test was used. *P < 0.05; **P < 0.01; ***P < 0.001; and ****P < 0.0001.