Absence of Nkx2-3 Homeodomain Transcription Factor Reprograms the Endothelial Addressin Preference for Lymphocyte Homing in Peyer’s Patches

Kellermayer, Zoltán; Mihalj, Martina; Lábadi, Árpád; Czömpöly, Tamás; Lee, Mike; O’Hara, Edward; Butcher, Eugene C.; Berta, Gergely; Balogh, András; Arnold, Hans Henning; Balogh, Péter

doi:10.4049/jimmunol.1402016

Cited by 14 publications

(21 citation statements)

References 42 publications

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“…In TNF-untreated bEnd.3 cells, both RA 1 and RA -T exosomes suppressed the expression of CCL28 and NKX2.3, the latter being an important transcription regulator for MAdCAM-1. 33,34 CCL25 expression was suppressed only by RA 1 T exosomes in TNF-untreated bEnd.3 cells ( Figure 5). These in vitro results may be only partially consistent with in vivo results observed in the small intestine, because bEnd.3 cells were originally derived from brain tissue.…”

Section: The Integrin A4b7 Displayed On Exosomes Supports Their Distrmentioning

confidence: 93%

“…A bioinformatics analysis using a TargetScan database predicted that 133 miRNAs would target gut-homing-related integrin-ligand or chemokine genes (supplemental Table 1; supplemental Figure 4). Although no miRNA candidates that targeted MAdCAM-1 were detected, several miRNAs predicted to target NKX2.3, a transcription factor critical in regulating the expression of MAdCAM-1, 33,34 were found. By using qPCR, we confirmed the upregulation of several miRNAs at increased levels in the RA 1 T exosomes ( Figure 6B).…”

Section: T Exosomes Reveals the Potential Candidates That Target Endomentioning

confidence: 97%

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Exosomal regulation of lymphocyte homing to the gut

Park¹,

Prajuabjinda²,

Soe³

et al. 2018

Blood Advances

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Exosomes secreted from T cells have been shown to affect dendritic cells, cancer cells, and other T cells. However, little is known about how T-cell exosomes (T exosomes) modulate endothelial cell functions in the context of tissue-specific homing. Here, we study the roles of T exosomes in the regulation of gut-specific T-cell homing. The gut-tropic T cells induced by retinoic acid secrete the exosomes that upregulate integrin α4β7 binding to the MAdCAM-1 expressed on high endothelial venules in the gut. T exosomes were preferentially distributed to the villi of the small intestine in an α4β7-dependent manner. Exosomes from gut-tropic T cells suppressed the expression of MAdCAM-1 in the small intestine, thereby inhibiting T-cell homing to the gut. Moreover, microRNA (miRNA) profiling analysis has shown that exosomes from gut-tropic T cells were enriched with miRNAs targeting NKX2.3, a transcription factor critical to MAdCAM-1 expression. Taken together, our study proposes that α4β7-expressing T exosomes distribute themselves to the small intestine and modify the expression of microenvironmental tissues such that any subsequent lymphocyte homing is precluded. This may represent a novel mechanism by which excessive lymphocyte homing to the intestinal tissues is downsized.

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Section: The Integrin A4b7 Displayed On Exosomes Supports Their Distrmentioning

confidence: 93%

Section: T Exosomes Reveals the Potential Candidates That Target Endomentioning

confidence: 97%

Exosomal regulation of lymphocyte homing to the gut

Park¹,

Prajuabjinda²,

Soe³

et al. 2018

Blood Advances

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“…Nkx2.3 2/2 mice showed delayed intestinal development coupled with malabsorption (11). Importantly, the development of PPs was also impaired, including the absence of MAdCAM-1 expression on HEVs (7,8), replaced by PNAd in adult mice (10). In humans, Nkx2.3 was linked to both CD and ulcerative colitis.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, the vascular specification of PPs is critically determined by the Nkx2.3 homeodomain transcription factor in a tissuespecific manner. In the absence of Nkx2.3 in mice, PPs and the spleen lack most of MAdCAM-1 (7,8) and exhibit a vasculature reminiscent of peripheral lymph nodes with peripheral node addressin (PNAd) + HEVs (9,10). In addition to its role in vascular specification of intestinal lymphoid tissues, Nkx2.3 also affects the maturation of villi, as its lack causes aberrant villus formation during the embryonic and early postnatal period of gut development.…”

mentioning

confidence: 99%

IL-22–Independent Protection from Colitis in the Absence of Nkx2.3 Transcription Factor in Mice

Kellermayer

Vojkovics

Dakah

et al. 2019

The Journal of Immunology

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The transcription factor Nkx2.3 regulates the vascular specification of Peyer patches in mice through determining endothelial addressin preference and may function as a susceptibility factor in inflammatory bowel diseases in humans. We wished to analyze the role of Nkx2.3 in colonic solitary intestinal lymphoid tissue composition and in colitis pathogenesis. We studied the colonic solitary intestinal lymphoid tissue of Nkx2.3-deficient mice with immunofluorescence and flow cytometry. Colitis was induced in mice using 2.5% dextran sodium sulfate, and severity was assessed with histology, flow cytometry, and quantitative PCR. We found that the lack of Nkx2.3 impairs maturation of isolated lymphoid follicles and attenuates dextran sodium sulfate-induced colitis independent of endothelial absence of mucosal addressin cell-adhesion molecule-1 (MAdCAM-1), which was also coupled with enhanced colonic epithelial regeneration. Although we observed increased numbers of group 3 innate lymphoid cells and Th17 cells and enhanced transcription of IL-22, Ab-mediated neutralization of IL-22 did not abolish the protection from colitis in Nkx2.3-deficient mice. Nkx2.3 2/2 hematopoietic cells could not rescue wild-type mice from colitis. Using LacZ-Nkx2.3 reporter mice, we found that Nkx2.3 expression was restricted to VAP-1 + myofibroblast-like pericryptal cells. These results hint at a previously unknown stromal role of Nkx2.3 as driver of colitis and indicate that Nkx2.3 + stromal cells play a role in epithelial cell homeostasis.

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“…Different forms of TNF receptor (TNFR) play different roles in SpA. TNFRI is related to both gut disease and arthritis; however, deletion of TNFRII ameliorated gut disease but exacerbated the joint inflammation in the TNF∆ARE mouse 28 model [165]. Interestingly, T cells only contribute to the development of IBD, but not arthritis in these mice [165].…”

Section: -54 Tnf Overexpressing Mousementioning

confidence: 99%

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

Tseng¹

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Ankylosing spondylitis (AS) is a chronic inflammatory arthritis characterised by severe inflammation of the axial skeleton followed by bone formation that can lead to ankylosis.The mechanisms mediating the transition from inflammation to bone formation are poorly understood due to the limited availability of relevant bone samples. Therefore, we used the proteoglycan-induced spondylitis (PGISp) mouse model to delineate the morphological changes during axial disease development. This mouse model develops spondylitis followed by ankylosis, mimicking the clinical progression seen in patients with AS.The first part of this project aimed to characterise the disease progression across a 43-week time-course in the PGISp mouse model. The principal assessment for analysing spinal disease was a semi-quantitative histological score that assessed joint inflammation, joint destruction (including intervertebral disc (IVD), cartilage and bone) and excessive tissue formation (peri-joint mesenchymal tissue expansion or fibrocartilage formation).Early inflammation initiated at the periphery of the IVD and was followed by varying levels of disc, cartilage and bone damage. In the advanced stages of disease, excessive tissue formation and ectopic chondrocyte expansion, ectopic bone and osteophyte formation were the key features. Abnormal tissue formation was always associated with IVD destruction, which was the result of inflammation, indicating that inflammation-derived IVD destruction is a prerequisite for induction of excessive tissue formation and the subsequent osteoproliferation.Current therapies for AS include non-steroidal anti-inflammatory drugs (NSAIDs), tumour necrosis factor (TNF) inhibitors and physiotherapy. However, these therapies aim to alleviate symptoms but cannot prevent syndesmophyte formation; hence new, more effective, therapeutic strategies are required. Genome-wide association studies have shown that AS is strongly associated with prostaglandin E2 (PGE2) receptor subtype 4 (EP4), which plays regulatory roles in both inflammation and bone formation. The involvement of EP4 in AS has not been examined. The second objective of this thesis was to examine the hypothesis that blocking EP4 can suppress disease progression by inhibiting both inflammation and bone formation. PGISp mice were prophylactically administered with ONO-AE1-329 (an EP4 agonist) or ONO-AE2-227 (an EP4 antagonist) ii for 16 weeks. Indomethacin, an NSAID, was included as a positive control of PGE2 signalling inhibitor. None of the treatments significantly altered peripheral arthritis or axial disease progression. Use of EP4 agonist or antagonist did not change bone mineral density and bone mineral content as measured by dual-energy X-ray absorptiometry. The

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Absence of Nkx2-3 Homeodomain Transcription Factor Reprograms the Endothelial Addressin Preference for Lymphocyte Homing in Peyer’s Patches

Cited by 14 publications

References 42 publications

Exosomal regulation of lymphocyte homing to the gut

Exosomal regulation of lymphocyte homing to the gut

IL-22–Independent Protection from Colitis in the Absence of Nkx2.3 Transcription Factor in Mice

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

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