An Essential Role of UBXN3B in B Lymphopoiesis

Abstract

Hematopoiesis is finely regulated to enable timely production of the right number and type of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential and new role of ubiquitin X domain containing gene 3B (UBXN3B) in balancing myelopoiesis and lymphopoiesis. Ubxn3b deficiency (Ubxn3b−/−) results in a remarkable increase in myeloid cells and neutrophil-to-lymphocyte ratio, along with a reduction in lymphocytes in steady-state mice. This dysregulation is exacerbated during viral infection and renders mice highly vulnerable to severe lung pathology induced by severe acute respiratory syndrome coronavirus 2 and arthritis by arthritogenic alphaviruses. Ubxn3b−/− mice present normal type I IFNs, higher viral loads and inflammatory mediators, lower virus-specific immunoglobulin G and slower resolution of disease, when compared to Ubxn3b+/+ littermates. Mechanistically, Ubxn3b−/− mice have fewer multipotent progenitors and common lymphoid progenitors, but more common myeloid progenitors. In particular, the precursor and immature B cell numbers are dramatically decreased in the bone marrow of Ubxn3b−/− mice. These data demonstrate that UBXN3B signaling is essential for restricting viral infection and immunopathogenesis by maintaining hematopoietic homeostasis.

Emerging roles for CNS fibroblasts in health, injury and disease

“…Despite these recent advances, we still know very little about the roles of CNS fibroblasts in the development and maintenance of the healthy, adult CNS and how they contribute to disease aside from fibrotic scarring. While we focus mostly on rodent studies in this Review, perivascular fibroblasts have been detected in human tumour samples 5 and associated with the vasculature of the human brain 6 , 7 , confirming that these cells are indeed present in the human CNS. Furthermore, perivascular fibroblasts have been shown to be dysfunctional in patients with amyotrophic lateral sclerosis (ALS) 8 .…”

“…To better define the molecular characteristics of perivascular and pial fibroblasts, single-cell RNA sequencing of fibroblasts isolated separately from adult leptomeninges and brain will be required. However, a recent preprint study reporting vessel isolation and nuclei extraction for sequencing (VINE-seq) in humans used annotations from other sequencing studies to detect distinct clusters of perivascular and meningeal fibroblasts 6 and found enriched expression of ECM components in perivascular fibroblasts whereas meningeal fibroblasts showed enriched expression of solute transporters 6 .…”

“…Even if fibroblasts are not engaged in scarring in these diseases, they could influence disease outcomes through signalling with nearby vascular cells. A preliminary study using VINE-seq to profile human vascular cells from the hippocampus and cortex of healthy individuals and patients with Alzheimer disease found dysregulation in IFNγ pathway and SMAD signalling genes in fibroblasts in Alzheimer disease 6 . In addition, in the pre-symptomatic stages of ALS, the fibroblast marker genes SPP1 and COLA6A1 are enriched and their protein products accumulate in perivascular spaces 8 .…”