Enforced Expression of Roquin Protein in T Cells Exacerbates the Incidence and Severity of Experimental Arthritis

Ji, Young Rae; Kim, Hei Jung; Yu, Dong Hoon; Bae, Ki Beom; Park, Seo Jin; Yi, Jun Koo; Kim, Nari; Park, Si Jun; Oh, Keon Bong; Hwang, Sung Ho; Lee, Sanggyu; Kim, Sung Hyun; Kim, Myoung Ok; Lee, Jeong-Woong; Ryoo, Zae Young

doi:10.1074/jbc.m112.374835

Cited by 18 publications

(18 citation statements)

References 40 publications

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“…How that balance is shifted in one direction or the other may ultimately determine the extent to which inflammation is mild or severe in those animals. It also will be of interest to determine the extent to which intestinal antigenic challenge following virus, bacteria, or parasite infection alters the inflammatory response locally and the extent to which this reflects the pathology seen in Crohn's disease, as recently reported for collagen-induced arthritis [29].…”

Section: Discussionmentioning

confidence: 99%

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

et al. 2013

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“…Tfh cells seem to be implicated in autoimmunity [18], and increased numbers are found in murine models of Systemic Lupus Erythematosus (SLE) [18]–[20] and inflammatory arthritis [21]; furthermore, strategies directed at reducing Tfh cell generation ameliorate disease manifestations in these animal models [20], [22].…”

Section: Introductionmentioning

confidence: 99%

Decreased Frequencies of Circulating Follicular Helper T Cell Counterparts and Plasmablasts in Ankylosing Spondylitis Patients Naïve for TNF Blockers

et al. 2014

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Follicular helper T cells (Tfh), localized in lymphoid organs, promote B cell differentiation and function. Circulating CD4 T cells expressing CXCR5, ICOS and/or PD-1 are counterparts of Tfh. Three subpopulations of circulating CD4+CXCR5+ cells have been described: CXCR3+CCR6- (Tfh-Th1), CXCR3-CCR6+ (Tfh-Th17), and CXCR3-CCR6- (Tfh-Th2). Only Tfh-Th17 and Tfh-Th2 function as B cell helpers. Our objective was to study the frequencies of circulating Tfh (cTfh), cTfh subsets and plasmablasts (CD19+CD20-CD27+CD38high cells), and the function of cTfh cells, in patients with Ankylosing Spondylitis (AS). To this end, peripheral blood was drawn from healthy controls (HC) (n = 50), AS patients naïve for TNF blockers (AS/nb) (n = 25) and AS patients treated with TNF blockers (AS/b) (n = 25). The frequencies of cTfh and plasmablasts were determined by flow cytometry. Cocultures of magnetically sorted CD4+CXCR5+ T cells with autologous CD19+CD27- naïve B cells were established from 3 AS/nb patients and 3 HC, and concentrations of IgG, A and M were measured in supernatants. We obseved that AS/nb but not AS/b patients, demonstrated decreased frequencies of circulating CD4+CXCR5+ICOS+PD-1+ cells and plasmablasts, together with a decreased (Tfh-Th17+Tfh-Th2)/Tfh-Th1 ratio. The amounts of IgG and IgA produced in cocultures of CD4+CXCR5+ T cells with CD19+CD27- B cells of AS/nb patients were significantly lower than observed in cocultures established from HC. In summary, AS/nb but not AS/b patients, demonstrate a decreased frequency of cTfh and plasmablasts, and an underrepresentation of cTfh subsets bearing a B helper phenotype. In addition, peripheral blood CD4+CXCR5+ T cells of AS/nb patients showed a decreased capacity to help B cells ex vivo.

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“…In contrast, Roquin overexpression in a collagen-induced arthritis model enhanced activation of CD28 and increased phosphorylation of Akt, JNK and IjB, which are downstream of CD28 [15]. CD28 is important in the early stages of T cell activation, whereas ICOS plays a major role in its maintenance.…”

Section: Discussionmentioning

confidence: 86%

“…Here, we showed that Roquin is expressed in liver and spleen after Con A injection, and that induction of hepatitis by Con A is enhanced in Roquin transgenic (Roquin Tg) mice relative to wild type (WT) mice. Roquin has previously been demonstrated to regulate the development of autoimmune diseases such as collagen-induced arthritis [15]; we have now expanded the group of conditions in which Roquin is known to play a role to include the acute inflammation that leads to T cellmediated liver injury.…”

Section: Discussionmentioning

confidence: 98%

“…In a previous study, transgenic overexpression of Roquin aggravated the severity of collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Roquin activates the CD28 signaling pathway and its component proteins, including Akt, JNK, and NF-jB, and upregulates production of several proinflammatory cytokines, such as TNF-a, IL-2, IL-6, and IFN-c [15].…”

Section: Introductionmentioning

confidence: 99%

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Enforced Expression of Roquin Protein in T Cells Exacerbates the Incidence and Severity of Experimental Arthritis

Cited by 18 publications

References 40 publications

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

Decreased Frequencies of Circulating Follicular Helper T Cell Counterparts and Plasmablasts in Ankylosing Spondylitis Patients Naïve for TNF Blockers

Over-expression of Roquin aggravates T cell mediated hepatitis in transgenic mice using T cell specific promoter

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