Abstract
Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquinsan/san mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquinsan/san mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquingt/gt mice) had small intestinal inflammation that mimicked that of Roquinsan/san mice. MLN cells in Roquinsan/san mice consisted of activated proliferating T cells, and had increased numbers of CD44hi CD62Llo KLRG1+ short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquinsan/san mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquinsan/san mice consisted of a high proportion of Gr-1+ T cells that included IL-17A+ cells and CD8+ IFN-γ+ cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquinsan/san mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn's disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process.
Highlights
Roquin, a Really Interesting New Gene (RING) finger E3 ubiquitin ligase that is characterized by a CCCH zinc finger found in RNA-binding proteins, localizes to cytosolic RNA granules that are involved in regulating mRNA stability and translation
Crohn’s disease (CD) is a form of inflammatory bowel disease (IBD) that can affect any region of the alimentary tract and may be associated with extra-intestinal inflammatory conditions such as iritis, arthritis, pulmonary inflammation, and skin disorders [8,11,12,13]
These include cytokine knockouts such as IL-22/2 and IL-102/2 mice [14,15], as well as models involving the transfer of effector T cells into immunodeficient mice [16,17]
Summary
A RING finger E3 ubiquitin ligase that is characterized by a CCCH zinc finger found in RNA-binding proteins, localizes to cytosolic RNA granules that are involved in regulating mRNA stability and translation. Initial characterization of Roquin-defective mice (Roquinsan/san), which have an M199R mutation in the Roquin protein, revealed chronic inflammation consisting of lymphadenopathy, splenomegaly, thrombocytopenia, necrotizing hepatitis, and increased numbers of CD4+ follicular T cells and ICOS expression [3,4]. The extent to which Roquin is involved in driving autoimmunity has been brought into question, by a recent study using complete and conditional Roquin knockout mice [6]. Conditional knockouts in which the Roquin defect was targeted to T cells failed to exhibit a breach in self-tolerance or have changes in follicular T cell differentiation, increased ICOS expression was noted [6]. The reason for the discrepancy between findings from Roquinsan/san and Roquin-deficient mice remains unclear; it is possible that a mutated form of the Roquin protein rather than total ablation of it is a contributing factor in promoting autoimmunity
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