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

Kellermayer, Zoltán; Vojkovics, Dóra; Dakah, Tareq Abu; Bodó, Kornélia; Botz, Bálint; Helyes, Zsuzsanna; Berta, Gergely; Kajtár, Béla; Schippers, Angela; Wagner, Norbert; Scotto, Luigi; O’Connor, Owen A.; Arnold, Hans Henning; Balogh, Péter

doi:10.4049/jimmunol.1801117

Cited by 7 publications

(14 citation statements)

References 45 publications

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“…In humans, the potential pathogenic role of the Nkx2-3 transcription factor was found in inflammatory bowel diseases (Crohn’s and ulcerative colitis) so far [ 23 , 24 ] and also suggested in spondylarthritis more recently [ 32 ]. In mice, the absence of Nkx2-3 proved to be protective in DSS-induced colitis through an IL-22-independent mechanism [ 18 ]. To our knowledge, this was the first experiment where the Nkx2-3 −/− mutation was investigated in the context of autoimmune arthritis.…”

Section: Discussionmentioning

confidence: 99%

“…Along with its role in the development of intestinal lymphoid tissues. Nkx2-3 is crucial for the expression and regulation of the mucosal addressin cell adhesion molecule-1 (MADCAM-1) on the spleen sinus lining cells and on high endothelial venules of the mesenteric lymph nodes and Peyer’s patches [ 17 , 18 , 19 , 20 ]. Nkx2-3 has an important role in spleen organization and function, since it controls the correct micro-environment for B cell maturation and T-cell-dependent (TD) immune reaction [ 14 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…In humans, overexpression of Nkx2-3 was found to be associated with both Crohn’s disease and ulcerative colitis through its effect on the regulation of PTPN2 expression, VEGF and MADCAM-1 signaling, and the production of endothelin-1 [ 16 , 18 , 23 , 24 ]. Additionally, Robles and colleagues reported that chromosomal translocation of Nkx2-3 gene alongside with immunoglobulin heavy chain gene ( IGH ), resulted in irregular B cell receptor signaling leading to the MZ B cell lymphomagenesis, through the activation of the NF-KB and PI3K-AKT pathways [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca2+ Influx in Nkx2-3 Knock-out Mice

Khanfar

Olasz

Gábris

et al. 2020

IJMS

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B cells play a crucial role in the pathogenesis of rheumatoid arthritis. In Nkx2-3-deficient mice (Nkx2-3−/−) the spleen’s histological structure is fundamentally changed; therefore, B cell homeostasis is seriously disturbed. Based on this, we were curious, whether autoimmune arthritis could be induced in Nkx2-3−/− mice and how B cell activation and function were affected. We induced arthritis with immunization of recombinant human proteoglycan aggrecan G1 domain in Nkx2-3−/− and control BALB/c mice. We followed the clinical picture, characterized the radiological changes, the immune response, and intracellular Ca2+ signaling of B cells. Incidence of the autoimmune arthritis was lower, and the disease severity was milder in Nkx2-3−/− mice than in control BALB/c mice. The radiological changes were in line with the clinical picture. In Nkx2-3−/− mice, we measured decreased antigen-induced proliferation and cytokine production in spleen cell cultures; in the sera, we found less anti-CCP-IgG2a, IL-17 and IFNγ, but more IL-1β, IL-4 and IL-6. B cells isolated from the lymph nodes of Nkx2-3−/− mice showed decreased intracellular Ca2+ signaling compared to those isolated from BALB/c mice. Our findings show that the transcription factor Nkx2-3 might regulate the development of autoimmune arthritis most likely through modifying B cell activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca2+ Influx in Nkx2-3 Knock-out Mice

Khanfar

Olasz

Gábris

et al. 2020

IJMS

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“…Interestingly, IBD (especially Crohn's disease) and AS share more risk alleles with each other than with other related autoimmune diseases, such as RA or coeliac disease 36,64 . Closer examination of the genetic risk factors for Crohn's disease and AS reveals certain factors to be shared, such as genes related to type 3 immunity and epithelial barrier integrity [65][66][67] (Fig. 2).…”

Section: Spa Is a Genetically Driven Diseasementioning

confidence: 99%

Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis

et al. 2020

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Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut-joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4β7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut-joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.

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“…Although the absence of Nkx2-3 causes transcriptional blockade of MAdCAM-1 expression ( 8 , 14 ), our previous studies indicated that the distribution of colonic lamina propria ILC3s in young adult mice are differentially affected in the lack of Nkx2-3 compared to the absence of MAdCAM-1 itself, so in Nkx2-3 −/− mice the colonic ILC3 number was higher, whereas in MAdCAM-1 −/− mice ILC3 numbers were significantly less ( 20 ). In this work first we sought to determine how these two different forms of MAdCAM-1 deficiency affect the postnatal population kinetics of ILC3s along the entire intestinal tract.…”

Section: Resultsmentioning

confidence: 99%

Differential Effects of the Absence of Nkx2-3 and MAdCAM-1 on the Distribution of Intestinal Type 3 Innate Lymphoid Cells and Postnatal SILT Formation in Mice

et al. 2019

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Seeding of leukocytes to developing lymphoid tissues in embryonic and early postnatal age and to the mucosa throughout adulthood depends on the interaction between endothelial MAdCAM-1 addressin and its cognate ligand α4β7 integrin. Nkx2-3 as a transcriptional regulator of MAdCAM-1 controls vascular patterning in visceral lymphoid tissues in mice, and has been identified as a susceptibility factor for inflammatory bowel diseases in humans, associated with lymphoid neogenesis in the inflamed intestines. The role of Nkx2-3 in the organogenesis of the solitary intestinal lymphoid tissues (SILTs) involving type 3 innate lymphoid cells (ILC3) is still unknown. Here we investigated the effect of Nkx2-3 on the postnatal distribution of intestinal ILC3s and the development of SILTs, comparing these to mice lacking MAdCAM-1, but preserving Nkx2-3. At 1 week of age small intestines (SI) contained significantly higher number of ILC3s relative to the colon, with a substantial reduction in MAdCAM-1−/− mice compared to C57BL/6 controls. One week later SI ILC3 number decreased in all genotypes, the number of colonic ILC3 of both Nkx2-3-deficient and Nkx2-3-heterozygous mice significantly increased. On the fourth postnatal week a further reduction of SI ILC3s was observed in both Nkx2-3-deficient and Nkx2-3-heterozygous mice, while in the colon the number of ILC3s showed a significant reduction in all genotypes. At 1 week of age only sporadic SILT components were present in all genotypes. By the second week mice deficient for either Nkx2-3 or MAdCAM-1 showed absence of SILT maturation compared to their relevant controls, lacking mature isolated lymphoid follicles (ILF). By the fourth week both Nkx2-3-deficient and Nkx2-3-heterozygous mice showed a similar distribution of ILFs relative to cryptopatches (CP), whereas in MAdCAM-1−/− mice CPs and immature ILFs were present, mature ILFs were scarce. Our data demonstrate that the complete absence of MAdCAM-1 partially impairs intestinal seeding of ILC3s and causes partial blockade of SILT maturation, without affecting peripheral lymph node development. In contrast, the inactivation of Nkx2-3 permits postnatal seeding, and its blocking effect on SILT maturation prevails at later stage, thus other adhesion molecules may compensate for the intestinal homing of ILC3s in the absence of MAdCAM-1.

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

Cited by 7 publications

References 45 publications

Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca2+ Influx in Nkx2-3 Knock-out Mice

Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca2+ Influx in Nkx2-3 Knock-out Mice

Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis

Differential Effects of the Absence of Nkx2-3 and MAdCAM-1 on the Distribution of Intestinal Type 3 Innate Lymphoid Cells and Postnatal SILT Formation in Mice

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