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 12

Treatment of the VEXAS-like symptoms by genetic loss of Morrbid.

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Treatment of the VEXAS-like symptoms by genetic loss of Morrbid. (A) S10...
(A) S100a8Cre-CKO mice were bred with Morrbid+/– mice to test the role of Morrbid in the autoinflammatory disease VEXAS syndrome. The human-mouse conserved long noncoding RNA (lncRNA) gene Morrbid is a prosurvival regulator for myeloid cells, especially for NEs, monocytes (MO), and eosinophils (EO). Similar to the homozygous Morrbid–/– mouse, the heterozygous mutant Morrbid+/– has a similarly shorter lifespan of myeloid cells. We generated the compound mutants S100a8Cre-CKO Morrbid+/– mice along with other control mice to determine the role of Morrbid in VEXAS syndrome. (B) Hair loss on the back and pigmentation on the paw knuckles were mitigated in the compound mutants S100a8Cre-CKO Morrbid+/– mice. Scale bars: 10 mm. (C) Hematological analysis of PB cells. MCV, NE counts, and NE percentages all showed a decreased trend, indicating the mitigation of VEXAS-like symptoms by genetic loss of Morrbid. (D) Serum levels of the proinflammatory cytokines IL-6, IL-1b, and TNF-α were downregulated in the compound-mutant S100a8Cre-CKO Morrbid+/– mice. Fold changes and P values are labeled in C and D. Data represent the mean ± SEM. P values were determined by Student’s t-test. n = 2~9 biological repeats per group.