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Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function. Intestinal dysbiosis is associated with an ever-growing list of autoimmune diseases. Here the authors show that both mice and humans with autoimmune arthritis can have dysbiosis and barrier leakiness prior to major signs of inflammatory arthritis, and treatment of mice with a zonulin antagonist can limit collagen-induced arthritis.

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis 1 . However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX 3 CR1 + tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX 3 CR1 − mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX 3 CR1 + lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease. Analysis of macrophage subsets within joints reveals a population of CX 3 CR1 + tissue-resident macrophages that form a tight-junction-mediated barrier at the synovial lining, protecting the joint from the invasion of inflammatory cells.

Krönke and colleagues show that the cytokine IL-23 controls the glycosylation profile and inflammatory activity of autoantibodies through control of sialyltransferase activity in plasma cells mediated by the T H 17 subset of helper T cells. The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the T H 17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, T H 17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23–T H 17 cell–dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.

Embryonic macrophages emerge before the onset of definitive hematopoiesis, seed into discrete tissues and contribute to specialized resident macrophages throughout life. Presence of embryonic macrophages in the bone marrow and functional impact on hematopoietic stem cells (HSC) or the niche remains unclear. Here we show that bone marrow macrophages consist of two ontogenetically distinct cell populations from embryonic and adult origin. Newborn mice lacking embryonic macrophages have decreased HSC numbers in the bone marrow suggesting an important function for embryo-derived macrophages in orchestrating HSC trafficking around birth. The establishment of a normal cellular niche space in the bone marrow critically depends on embryonic macrophages that are important for the development of mesenchymal stromal cells, but not other non-hematopoietic niche cells, providing evidence for a specific role for embryo-derived macrophages in the establishment of the niche environment pivotal for the establishment of a normally sized HSC pool. Haematopoietic stem cells (HSC) are responsible for blood cell generation and reside in the bone marrow. Here, the authors show that macrophages in the bone marrow originate from embryonic or adult haematopoietic lineages and that embryo-derived macrophages are important for the establishment of the HSC pool.

Closed circulatory systems underlie the function of vertebrate organs, but in long bones their structure is unclear although they constitute the exit route for bone marrow (BM) leukocytes. To understand neutrophil migration from BM, we studied the vascular system of murine long bones. Here, in a mouse model, we show that hundreds of capillaries originate in BM, traverse cortical bone perpendicularly along the shaft and connect to the periosteal circulation. Structures similar to these trans-cortical vessels (TCVs) also exist in human limb bones. TCVs express arterial or venous markers and transport neutrophils. Furthermore, over 80% of arterial and 59% of venous blood passes through TCVs. Genetic and drug-mediated modulation of osteoclast count and activity leads to substantial changes in TCV numbers. In a murine model of chronic arthritic bone inflammation, new TCVs develop within weeks. Our data indicate that TCVs are a central component of the closed circulatory system in long bones and may represent an important route for immune cell export from BM. Bone marrow-derived cells can rapidly enter the systemic circulation, but how this is achieved is unclear. Grüneboom et al. identify tiny capillaries, termed trans-cortical vessels (TCVs), that connect the bone marrow cavity to the systemic vasculature, and show that the majority of blood in long bones passes through TCVs.

The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the T 17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, T 17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-T 17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.

BackgroundGlucocorticoid (GC) therapy is frequently used to treat rheumatoid arthritis due to potent anti-inflammatory actions of GCs. Direct actions of GCs on immune cells were suggested to suppress inflammation.ObjectivesDefine the role of the glucocorticoid receptor (GR) in stromal cells for suppression of inflammatory arthritis.MethodsBone marrow chimeric mice lacking the GR in the hematopoietic or stromal compartment, respectively, and mice with impaired GR dimerisation (GRdim) were analysed for their response to dexamethasone (DEX, 1 mg/kg) treatment in serum transfer-induced arthritis (STIA). Joint swelling, cell infiltration (histology), cytokines, cell composition (flow cytometry) and gene expression were analysed and RNASeq of wild type and GRdim primary murine fibroblast-like synoviocytes (FLS) was performed.ResultsGR deficiency in immune cells did not impair GC-mediated suppression of STIA. In contrast, mice with GR-deficient or GR dimerisation-impaired stromal cells were resistant to GC treatment, despite efficient suppression of cytokines. Intriguingly, in mice with impaired GR function in the stromal compartment, GCs failed to stimulate non-classical, non-activated macrophages (Ly6Cneg, MHCIIneg) and associated anti-inflammatory markers CD163, CD36, AnxA1, MerTK and Axl. Mice with GR deficiency in FLS were partially resistant to GC-induced suppression of STIA. Accordingly, RNASeq analysis of DEX-treated GRdim FLS revealed a distinct gene signature indicating enhanced activity and a failure to reduce macrophage inflammatory protein (Mip)-1α and Mip-1β.ConclusionWe report a novel anti-inflammatory mechanism of GC action that involves GR dimerisation-dependent gene regulation in non-immune stromal cells, presumably FLS. FLS control non-classical, anti-inflammatory polarisation of macrophages that contributes to suppression of inflammation in arthritis.

BackgroundCheckpoints and mechanisms regulating the onset of rheumatoid arthritis (RA) remain largely elusive. Apart from B cells and auto-antibodies, Th17 cells were shown to critically contribute to disease development. Mice lacking IL-23, a cytokine controlling the pathogenicity of Th17 cells, are completely protected against arthritis. Yet, the exact role of the IL-23/Th17 axis during this autoantibody-driven disease remain incompletely understood.Material and methodsIL23A-/- mice and mice receiving an IL23 blocking antibody were analysed during active and passive arthritis models including collagen-induced arthritis (CIA), the K/BxN arthritis model, collagen-antibody induced arthritis (CAIA) and K/BxN-serum transfer arthritis. Both clinical, histological and immunological parameters of arthritis were assessed. IgG glycosylation was analysed using the MALDI-TOF technique. IgG activity was determined by measuring the cytokine release of immune-complex-stimulated myeloid cells. To study the crosstalk between B cells and Th17 cells, co-culture experiments were performed.ResultsHere we report, that the IL-23/Th17 axis did not directly contribute to auto-antibody induced inflammation within inflamed joints, but controlled the glycosylation profile and inflammatory activity of auto-antibodies during the prodromal phase of disease. Th17 cells were found to accumulate in germinal centres auf secondary lymphatic organs prior to onset of experimental arthritis, where they suppressed the expression of β-glactoside α2,6-sialyltransferase 1 (St6gal1) in differentiating plasmablasts. The consecutive change in the immunoglobulin G (IgG) glycosylation profile provoked a shift towards a pro-inflammatory autoantibody repertoire and triggered the inflammatory phase of arthritis. Plasmablasts of RA patients similarly displayed a decreased St6gal1 activity, while IgG from these individuals showed corresponding changes in its glycosylation profile as well as an increased inflammatory activity, suggesting that related pathways might contribute to onset and progression of autoantibody-mediated diseases in humans.ConclusionOur current findings identify a novel IL-23/Th17-dependent checkpoint that controls autoantibody activity, unmasks a preexisting breach in humoral tolerance, and initiates the transition from a stage of asymptomatic autoimmunity into inflammatory autoimmune disease.

BackgroundCheckpoints and mechanisms regulating the onset of rheumatoid arthritis (RA) remain largely elusive. Apart from B cells and auto-antibodies, Th17 cells were shown to critically contribute to disease development. Mice lacking IL-23, a cytokine controlling the pathogenicity of Th17 cells, are completely protected against arthritis. Yet, the exact role of the IL-23/Th17 axis during this autoantibody-driven disease remain incompletely understood.Material and methodsIL23A-/- mice and mice receiving an IL23 blocking antibody were analysed during active and passive arthritis models including collagen-induced arthritis (CIA), the K/BxN arthritis model, collagen-antibody induced arthritis (CAIA) and K/BxN-serum transfer arthritis. Both clinical, histological and immunological parameters of arthritis were assessed. IgG glycosylation was analysed using the MALDI-TOF technique. IgG activity was determined by measuring the cytokine release of immune-complex-stimulated myeloid cells. To study the crosstalk between B cells and Th17 cells, co-culture experiments were performed.ResultsHere we report, that the IL-23/Th17 axis did not directly contribute to auto-antibody induced inflammation within inflamed joints, but controlled the glycosylation profile and inflammatory activity of auto-antibodies during the prodromal phase of disease. Th17 cells were found to accumulate in germinal centres auf secondary lymphatic organs prior to onset of experimental arthritis, where they suppressed the expression of beta -glactoside alpha 2,6-sialyltransferase 1 (St6gal1) in differentiating plasmablasts. The consecutive change in the immunoglobulin G (IgG) glycosylation profile provoked a shift towards a pro-inflammatory autoantibody repertoire and triggered the inflammatory phase of arthritis. Plasmablasts of RA patients similarly displayed a decreased St6gal1 activity, while IgG from these individuals showed corresponding changes in its glycosylation profile as well as an increased inflammatory activity, suggesting that related pathways might contribute to onset and progression of autoantibody-mediated diseases in humans.ConclusionOur current findings identify a novel IL-23/Th17-dependent checkpoint that controls autoantibody activity, unmasks a preexisting breach in humoral tolerance, and initiates the transition from a stage of asymptomatic autoimmunity into inflammatory autoimmune disease.