UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice
Ge Dong, Jingjing Liu, Wenyan Jin, Hongxi Zhou, Yuchen Wen, Zhiqin Wang, Keyao Xia, Jianlin Zhang, Linxiang Ma, Yunxi Ma, Lorie Chen Cai, Qiufan Zhou, Huaquan Wang, Wei Wei, Ying Fu, Zhigang Cai
Ge Dong, Jingjing Liu, Wenyan Jin, Hongxi Zhou, Yuchen Wen, Zhiqin Wang, Keyao Xia, Jianlin Zhang, Linxiang Ma, Yunxi Ma, Lorie Chen Cai, Qiufan Zhou, Huaquan Wang, Wei Wei, Ying Fu, Zhigang Cai
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Research Article Hematology Inflammation

UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice

Abstract

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a hemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells (HSCs). The pathogenic cell type(s) responsible for the syndrome are unknown, and murine models recapitulating the disease are lacking. We report that loss of Uba1 in various mouse hematopoietic cell types resulted in pleiotropic consequences and demonstrate that an approximate 70% loss of Uba1 in neutrophils (NEs) of murine mutants induced nonlethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induced extensive hematopoietic cell loss, whereas depletion of Uba1 in B cells, T cells, or megakaryocytes induced corresponding cell death, but these mutant mice appeared normal. Depletion of Uba1 in monocytes and NEs failed to induce cell death, and the mutant mice were viable. Among the tested models, only depletion of Uba1 in NEs induced autoinflammatory symptoms including increased counts and percentages of NEs, increased proinflammatory cytokines, presence of vacuoles in myeloid cells, splenomegaly, and dermatitis. Residual Uba1 was approximately 30% in the mutant NEs, which disrupted cellular hemostasis. Finally, genetic loss of the myeloid prosurvival regulator Morrbid partially mitigated the VEXAS-like symptoms. The established VEXAS-like murine model will further our understanding and treatment of the newly identified autoinflammatory syndrome prevalent among aged men.

Authors

Ge Dong, Jingjing Liu, Wenyan Jin, Hongxi Zhou, Yuchen Wen, Zhiqin Wang, Keyao Xia, Jianlin Zhang, Linxiang Ma, Yunxi Ma, Lorie Chen Cai, Qiufan Zhou, Huaquan Wang, Wei Wei, Ying Fu, Zhigang Cai

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Figure 13

Summary of the study and a comparison with VEXAS-related clinical studies.

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Summary of the study and a comparison with VEXAS-related clinical studie...
(A and B) Normal hematopoiesis (A) and VEXAS-conditioned hematopoiesis (B). According to the published clinical results, as summarized in the lower panel of B, patients with VEXAS manifest 3 typical features. (i) Somatic and pathogenic UBA1 point mutation in HSCs (typically at the M41 site, indicating a loss of the cytoplasm isoform UBA1b). The VEXAS-like outcomes are likely attributable to the combination effect of all blood cells. (ii) Autoinflammatory symptoms at older ages (around ≥40 years of age for older males). (iii) Increased VAF of mutant UBA1 and occurrence of clonal hematopoiesis. (C–E) The outcomes of 9 different CKO lines used in the study are summarized in C, D, and E. Except for monocytes and NEs, we demonstrate that most of the hematopoietic progenitor and mature cells were not tolerant of the null-version mutation of Uba1. Importantly, we demonstrate that monocytes and NEs survived with an approximately 30% residual level of Uba1. However, monocyte depletion of Uba1 in Lyz2Cre-CKO and Cx3cr1Cre-CKO mice did not lead to VEXAS-like symptom development like in NE depletion of Uba1 in S100a8Cre-CKO mice. As summarized in the lower panel of E, VEXAS-like symptoms in S100a8Cre CKO mice also included 3 typical features. (i) A null version of Uba1 mutation in NEs, indicating that both nucleic and cytoplasm isoforms were deficient and that the effect was mainly attributable to the mutant NEs. (ii) Autoinflammatory symptoms were typically apparent at 4 months of age and extended to older ages (i.e., ≥6 months of age), but the lifespan of the S100a8Cre-CKO mutant animals was grossly normal. (iii) The cBMT experiments showed increased fraction of mutant NEs and the occurrence of clonal hematopoiesis. See also the Discussion in the main text and Supplemental Tables 1–4 for further comparisons through different angles.