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G. Hernandez et al.
decreased expression of aberrantly activated myeloid line- age genes in HSC from CIA mice, including PU.1 and tar- gets such as Csfr2b, Itgam, as well as Il1r1 and the myeloid transcription factor Irf8 (Figure 7E), consistent with reduced myeloid expansion in anakinra-treated CIA mice. Taken together, these data indicate that inflammation-dri- ven myeloid and proliferation arrest gene programs in HSC are at least partially reversible, and can be alleviated by cytokine blockade therapy.
Discussion
Human RA is associated with deregulations in the blood system that can contribute to disease pathogenesis and patient morbidity.14,15,33 Here, we used the CIA mouse model of human RA to better understand the impact of disease and therapeutic intervention on the hematopoietic system. We found that CIA induced a profoundly myeloid-skewed hematopoietic hierarchy characterized
ABC
D
E
Figure 7. Cytokine blockade attenuates inflammation-induced hematopoietic stem cell gene programs. (A) Experimental design. (B) Representative FACS plots and (C) cell cycle distribution of hematopoietic stem cells (HSC) from control mice (Ctrl), mice with collagen-induced arthritis (CIA) and CIA mice treated with anakinra (+Ana) (n=5 per group). (D) Fluidigm analysis of proliferation arrest gene programs in HSC from Ctrl, CIA and CIA +Ana mice. The data are presented as log10 fold expression versus Ctrl HSC (n=12-16 per group). (E) Fluidigm analysis of myeloid gene expression in HSC from Ctrl, CIA and CIA +Ana mice. The data are presented as log10 fold expression versus Ctrl HSC. Ct values were normalized to Actb (n=12-16 per group). The data are presented as log10 fold expression versus Ctrl HSC (n=12-16 per group). The data were compiled from two independent experiments. *P<0.05; **P<0.01 ***P<0.001, ****P<0.0001 as determined by one-way analysis of variance or the Mann-Whitney U-test. BM: bone marrow.
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haematologica | 2020; 105(3)