A20 deficiency in hematopoietic stem cells causes lymphopenia and myeloproliferation due to elevated Interferon-\u03b3 signals

Masahiro Marshall Nakagawa,Chozha Vendan Rathinam

doi:10.1038/s41598-019-49038-8

Masahiro Marshall Nakagawa, Chozha Vendan Rathinam

Open Access

https://doi.org/10.1038/s41598-019-49038-8

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Abstract

Inflammation and inflammatory cytokines have been shown to exert both positive and negative effects on hematopoietic stem cells (HSCs) and hematopoiesis. While the significance of inflammation driven hematopoiesis has begun to unfold, molecular players that regulate this phenomenon remain largely unknown. In the present study, we identified A20 as a critical regulator of inflammation controlled hematopoietic cell fate decisions of HSCs. A20 deficiency in HSCs leads to increased differentiation of myeloid cells and myeloproliferation. Analysis of erythroid lineage cells of A20 deficient mice indicated a striking reduction of erythrocytes in the bone marrow (BM), but elevated numbers in the spleen. Loss of A20 in HSCs causes a severe blockade of B cell differentiation in the BM and absence of peripheral B cells in the spleen, liver and blood. T cell differentiation studies revealed a reduction of both T cell progenitors and differentiated T cells in the thymus and altered T cell numbers in the spleens of A20 mutant mice. Analysis of lineage committed progenitors of the myeloid, erythroid and lymphoid lineages specified an altered composition in the A20 deficient BM. Genetic studies identified that specific loss of A20 in the myeloid lineage cells results in myeloproliferation. Bone marrow transplantation studies and mixed bone marrow chimera studies suggested an involvement of inflammatory cytokines, particularly interferon (IFN)- γ, in the onset of myeloproliferation and lymphopenia of A20 deficient mice. Finally, ablation of IFNγ signals in A20 deficient mice rescued the hematopoietic defects. In essence, these studies highlight a previously unknown role for A20 in the restriction of inflammation driven pathologic hematopoiesis. We believe that our studies based on A20 mutant mice will be helpful in understanding the pathophysiology and in the treatment of patients with A20 (TNFAIP3) mutations.

Highlights

Hematopoiesis is a process through which blood cells are constantly generated and replenished in the body
Even though we have recently shown that deficiency of A20 leads to loss of quiescence and maintenance of hematopoietic stem cells (HSCs) due to exaggerated IFNγ signals[11], it was unknown if exaggerated IFNγ mediated signals are responsible for the onset of myeloproliferation and lymphopenia caused by A20 deficiency
In an attempt to identify the functions of the ubiquitin editing enzyme A20 in HSCs, we previously generated mice that lack A20 in HSCs, by crossing A20 F/F mice with Vavcre/+ transgenic mice to generate A20F/F Vavcre/+ (A20Hem-KO)[11,22]

Summary

Introduction

Hematopoiesis is a process through which blood cells are constantly generated and replenished in the body. Loss functions mediated by the E3 ubiquitin ligase c-Cbl results in compromised HSC functions[7], age related myeloproliferation and lymphopenia[8], and the onset of acute myeloid leukemia[9]. Deficiency of another HECT type E3 ubiquitin ligase-Itch causes abnormal hematopoiesis[10]. Mx1-Cre or ERT2-Cre mediated ablation of A20 in mice resulted in increased myeloid differentiation and rapid B cell apoptosis[21] While all these studies have highlighted the importance of A20 in the functions of specific immune cell types, it remained unclear if A20 has any roles on hematopoietic differentiation, especially at the earlier stages of myeloid, erythroid and lymphoid lineages. Our data demonstrate that ablating IFNγ signals is sufficient to rescue the pathologic hematopoiesis caused by A20 deficiency

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