Disturbing immune homeostasis by neutrophil loss of Uba1 induces VEXAS-like autoinflammatory disease in mice

Abstract

ObjectiveVEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an identified haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells. We report Uba1 loss in various mouse hematopoietic cell types leads to diverse effects, with approximately 70% Uba1 depletion in neutrophils inducing non-lethal VEXAS-like symptoms. MethodsUsing nine different Cre/flox-mediated conditional-knockout (CKO) models, we interrogated the phenotypes caused by hematopoietic loss of Uba1. Neutrophil-specific depletion of Uba1 were validated and VEXAS-like phenotypes were examined. ResultsUba1 loss in HSCs induces extensive hematopoietic cell death while in B or T cells, or megakaryocytes induces corresponsive cell death but these mutants appear normal. Uba1 loss in monocytes and neutrophils failed to induce cell death and the mutants are viable. Among the models, only Uba1 loss in neutrophils manifests autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, vacuoles in myeloid cells and dermatitis. Residual Uba1 is about 30% in the mutant neutrophils, which manifest disturbed cellular hemostasis. Genetic loss of Morrbid partially mitigated the VEXAS-like symptoms. ConclusionOur study reveals diverse effects of Uba1 loss in hematopoietic cells and establishes a VEXAS-like murine model, facilitating understanding and potential treatments for this syndrome prevalent in aged men. HIGHLIGHTSO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSVEXAS syndrome is a recently identified hematological and immunological disease prevalent in adult man but rarely in adult woman. Somatic mutations in the E1-enzyme encoding gene UBA1 in hematopoietic stem cells is the driver on the top of the genetic etiology of the disease. However, the major pathogenic cell type(s) for VEXAS syndrome has not been experimentally examined and mouse models recapitulating the disease are lacking. WHAT THIS STUDY ADDSO_LIUsing nine different conditional-knockout (CKO) murine models, we interrogated the pleiotropic phenotypes caused by loss of the ubiquitin activation enzyme Uba1 in different hematopoietic cell types; C_LIO_LIOur results demonstrated that among the nine tested CKO mutants, only neutrophil loss of Uba1 results in VEXAS-like autoinflammatory disease; C_LIO_LIThe VEXAS-like symptoms in the S100a8Cre-CKO mutant mice include: increased counts of white blood cells and neutrophils, increased percentage of neutrophils, increased serum level of proinflammatory cytokines (IL-1{beta}, IL-6 and TNF), observation of vacuoles, increased survival, and increased phagocytosis in mutant neutrophils; C_LIO_LIPharmacological treatments with IL-1 inflammatory pathway inhibitors Anakinra or Canakinumab or genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms in the S100a8Cre-CKO mutants; C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThe study reports a technical strategy of developing the murine models for VEXAS syndrome. In addition, the study dissects cellular and molecular mechanisms, especially the cell-type-dependent tolerance and pathogenicity of loss of function of Uba1, for the occurrence of the autoinflammation diseases in mice. The study provides translational implications in etiology and potential treatment choices for the newly-identified haemato-rheumatoid syndrome in clinical management.