Background Gut derived innate lymphoid cells of type 3 (ILC)3 are increased in number in the circulation and inflamed tissues of AS patients. Factors influencing the maintainace of ILC3 in an activated status are not clear. The atypical chemokine receptor D6 is a decoy and scavenger receptor for most inflammatory CC chemokines and acts preventing exacerbated inflammatory reactions. Mice lacking D6 expression in the non-hematopoietic compartment display a significant increase of pro-inflammatory monocytes in the peripheral blood and in secondary lymphoid tissues. The role of D6 in human inflammatory disorders has not been inverstigated.
Objectives To evaluate whether modulation of D6 expression occurs in the gut and in BM of AS patients and accompanied with a selective increase of pro-inflammatory CXCR1highLy6highTL1A+CCR7+ cells in the circulation and inflamed tissues of AS and to study the effect of these cells in modulating ILC3 differentiation.
Methods RT-PCR and immunohistochemistry were used to evaluate the expression of D6 in the gut and bone marrow of AS patients and controls. Different monocyte substes were analyzed by flow cytometry in the peripheral blood, gut, synovial fluids and bone marrow of AS patients and controls. Isolated peripheral CXCR1highLy6highTL1A+CCR7+ cells were co-coltured with isolated peripheral ILC3 and changes in ILC3 frequency were evaluated by flow cytometry.
Results D6 was significantly down-regulated in the ileum and in the bone marrow of AS patients compared to controls. D6 deficiency was accompanied by a complex monocyte/macrophage signature. Tissue resident CXCR1highLy6low macrophages were expanded in the ileum of AS patients compared to controls. A significant increase in the frequency of pro-inflammatory CXCR1highLy6high monocytes producing high levels of TL1A and IL-23 was observed in the ileum of AS patients. In the peripheral blood a statistically significant increase in the frequencies of both bone marrow derived CXCR1lowLy6High and intestinal derived CXCR1highLy6highCCR7+TL1A+IL-23+ monocytes, the latest being also expanded in AS synovial fluids and bone marrow. Isolated pro-inflammatory CXCR1highLy6highTL1A+IL-23+CCR7+ monocytes from peripheral blood of AS induced the expansion and activation, evaluated through the production of IL-22 and IL-17, of ILC3.
Conclusions In this study we provide the first demonstration that absence of D6 expression in the gut and in the inflamed tissues of AS patients selectively induced the intestinal accumulation and re-circulation of pro-inflammatory CXCR1highLy6highTL1A+IL-23+CCR7+ monocytes. Since the ability of these cells in promoting ILC3 expansion and activation, these cells may promote a sustained pro-inflammatory status in AS.
Disclosure of Interest None declared
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