UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice
Ge Dong, … , Ying Fu, Zhigang Cai
Ge Dong, … , Ying Fu, Zhigang Cai
Published September 4, 2025
Citation Information: J Clin Invest. 2025;135(21):e193011. https://doi.org/10.1172/JCI193011.
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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 1

Conditional depletion of Uba1 in mice.

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Conditional depletion of Uba1 in mice. (A) A brief introduction of VEXAS...
(A) A brief introduction of VEXAS syndrome occurrence in the clinic and in the present study using CKO mouse models. VAF, variant allele fraction. (B) Gene structure of Uba1 in mice and the CKO strategy in the present study. The mouse Uba1 locus is in the X-chromosome as human UBA1. Left panel: Gene structure of Uba1 in the WT allele and the fl knock-in allele. Right panel: The primers F1/R1 were used to distinguish the WT and fl alleles in the PCR genotyping. (C) Disruption of Uba1 transcripts was revealed by sequencing read alignment in the bulk RNA-Seq BM cell datasets. The S100a8Cre-CKO mice were used here for transcriptional chimerism analysis. (D) Expression of Uba1 protein in total BM cells by an antibody specific to the Uba1a isoform. Note that no truncated Uba1a protein was detected (arrow marks the predicted molecular weight of the putative truncated isoform, 22 kDa). Three biological repeats (R1, R2, and R3) were used for WT and CKO mice. (E) Expression of the Uba1 isoform in purified NEs by the Uba1a-specific antibody. Note that the residual level of Uba1a in NEs isolated from S100a8Cre-CKO BM was approximately 28% of that in WT controls (P = 0.0001). Again, no truncated Uba1a protein was detected (arrow, 22 kDa). (F) NE depletion of Uba1a and Uba1b isoforms determined by an alternative antibody sensitive to the 2 Uba1 isoforms. Note that the residual level of Uba1 (2 isoforms in total) in S100a8Cre-CKO BM was approximately 31% of that in WT controls (P = 0.012). (G) Expression of the 2 Uba1 isoforms (Uba1a and Uba1b) in primary BM cells of WT and S100a8Cre-CKO mice, in the mouse cell line Raw264.7, and in the 2 human cell lines K562 and 293T. *P < 0.05 and ****P < 0.0001, by Student’s t-test. n = 3~6 biological repeats. R1/R2/R3 indicates 3 independent biological repeats.