Tolerogenic XCR1+ dendritic cell population is dysregulated in HLA-B27 transgenic rat model of spondyloarthritis

Abstract

BackgroundSpondyloarthritis (SpA) is a chronic inflammatory disease affecting primarily axial and peripheral joints and sometimes also extra-articular organs, such as the gut. Rats transgenic for HLA-B27 and human β2-microglobulin (B27-Tg rat) develop clinical manifestations resembling human disease. In this model, it has been shown that CD103+ conventional dendritic cells (cDCs) exhibited altered functions, likely promoting SpA development. CD4− cDC subpopulation expressing XCR1, a chemokine receptor involved in their migration, have been described to be tolerogenic in steady state. Thus, in this study, we wished to examine the fate of XCR1+ cDCs in this animal model of SpA.MethodscDC populations were isolated from the spleen, mesenteric lymph nodes (MLN), and colonic lamina propria from B27-TG and control nontransgenic (NTG) and/or HLA-B7 transgenic rats after collagenase digestion and density gradient and characterized with flow cytometry or real-time PCR. Migration of cDCs from intestinal mucosa to MLN was assessed, using TLR-7 stimulation with Resiquimod.ResultsWe observed a reduced frequency of cCD4− DCs in B27-Tg rats, as compared to control rats. Furthermore, such decrease was not due to excessive death of CD4− cDCs in B27-Tg rats. Interestingly, we observed a decrease frequency of the XCR1+ subpopulation among CD4− cDCs in the spleen, MLN, and lamina propria from B27-Tg rats. Finally, after TLR-7 stimulation, the migration of XCR1+ cDCs to MLN was proportionally reduced in B27-Tg rats.ConclusionOur results demonstrate for the first time a decreased proportion of the tolerogenic XCR1+ cDC subpopulation in SpA target organs in B27-Tg rat, which may affect the maintenance of self-tolerance and control of inflammation.Electronic supplementary materialThe online version of this article (10.1186/s13075-019-1827-9) contains supplementary material, which is available to authorized users.

Lessons on SpA pathogenesis from animal models

“…Looking in more details at cDC subpopulations, an imbalance was found between the cDC2 subset -implicated in T cell activation and cytokines production-and cDC1 -critical for tolerance induction-marked by a decreased proportion of the latter in the spleen, the mesenteric lymph nodes and the lymph draining the gut [29,36]. This could at least in part be related to the defective migration of cDC1 from the colonic mucosa to mesenteric lymph nodes, possibly due to cytoskeleton alteration [36].…”

“…Looking in more details at cDC subpopulations, an imbalance was found between the cDC2 subset -implicated in T cell activation and cytokines production-and cDC1 -critical for tolerance induction-marked by a decreased proportion of the latter in the spleen, the mesenteric lymph nodes and the lymph draining the gut [29,36]. This could at least in part be related to the defective migration of cDC1 from the colonic mucosa to mesenteric lymph nodes, possibly due to cytoskeleton alteration [36]. Of particular interest was a relative decrease in all the organs studied and an altered capacity to support in vitro Treg differentiation, of the XCR1+ cDC1 subset, known to promote the induction of peripheral Treg by the production of transforming growth factor-β1 (TGF1) and retinoic acid from vitamin A [36,37].…”

“…This could at least in part be related to the defective migration of cDC1 from the colonic mucosa to mesenteric lymph nodes, possibly due to cytoskeleton alteration [36]. Of particular interest was a relative decrease in all the organs studied and an altered capacity to support in vitro Treg differentiation, of the XCR1+ cDC1 subset, known to promote the induction of peripheral Treg by the production of transforming growth factor-β1 (TGF1) and retinoic acid from vitamin A [36,37]. Besides, the cDC2 subset from disease-prone HLA-B27 transgenic lines displayed a down-regulation of Interferon gamma (Ifng) and IFN-regulated genes at the transcriptomic level that could be secondary to an induction of suppressor of cytokine signaling (Socs)3 gene.…”

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

“…The same study further showed that myeloid cells with a similar phenotype were found to be expanded in the SKG mouse model. In the HLA-B27-transgenic rat model of SpA, colonic tolerogenic (XCR1 + ) dendritic cells were reduced in HLA-B27-transgenic rats (as compared with control rats) and had a reduced capacity to induced T reg cell differentiation 166 . The results of these studies of myeloid cells should prompt in-depth phenotyping studies using next-generation technologies.…”

STAT3 and SPI1, may lead to the immune system dysregulation and heterotopic ossification in ankylosing spondylitis

“…AS's pathogenesis is multifactorial, involving multiple cell types, cellular processes, and molecular mediators and regulators [ 4 , 5 ]. Studies show that the major histocompatibility complex region (MHC) is closely related to AS, and about 95% AS patients are born with a gene named HLA-B27 [ 6 ]. However, HLA-B27 predisposition fails to fully explain the cause of the disease, and this leads to a strong effort to identify additional predisposing factors.…”