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 9

NE-specific depletion of Uba1 in S100a8Cre-CKO BM revealed by scRNA-Seq analysis of BM cells.

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NE-specific depletion of Uba1 in S100a8Cre-CKO BM revealed by scRNA-Seq ...
(A) BM cells from Uba1fl/y (WT) and S100a8Cre-CKO mice were subject for scRNA-Seq analysis. A total of 11 major hematopoietic cell types were annotated in the uniform manifold approximation and projection (UMAP) plot for dimension reduction. Of note, 2 types of NEs are highlighted: pro-NEs and NEs. As shown in the right panel, expression of Ms4a3 (marker for GMP cells) and Cebpd (marker for primitive and mature NEs) marks the developmental continuity from HSPCs/GMPs to NEs. pDC, plasmacytoid dendritic cell. (B) Expression of Uba1 in HSPCs, monocytes (Mono), pro-NEs, and NEs were quantified in Uba1fl/y (WT) and S100a8Cre-CKO scRNA-Seq datasets. Note that there is no reduction of Uba1 expression in HSPCs from the S100a8Cre-CKO (residual level: 104%), a slight decrease of Uba1 in monocytes (residual level: 82%) and a dramatic decrease of Uba1 in pro-NEs or in NEs (residual levels: 27% and 29%, respectively). Each single cell of the indicated cell types was included for the Uba1 expression analysis. ****P < 0.0001, by Student’s t-test.