Proinflammatory CX3CR1+CD59+Tumor Necrosis Factor–Like Molecule 1A+Interleukin‐23+ Monocytes Are Expanded in Patients With Ankylosing Spondylitis and Modulate Innate Lymphoid Cell 3 Immune Functions

Abstract

Objective Gut‐derived innate lymphoid cell 3 (ILC3) has been shown to participate in the pathogenesis of ankylosing spondylitis (AS). CX3CR1+ mononuclear phagocytes (MNPs) have been demonstrated to modulate ILC3 function in the gut. This study was undertaken to investigate the role of proinflammatory CX3CR1+CD59+ MNPs in modulating ILC3 function in AS patients. Methods MNP subsets in the blood of AS patients and controls were analyzed by flow cytometry. The presence of CX3CR1+CD59+ cells in tissue was confirmed by confocal microscopy. Expression of the proinflammatory chemokines CX3CL1 and CCL2 and decoy receptor 6 (DcR‐6) was analyzed. Peripheral CX3CR1+CD59+ cells were cocultured with ILC3, and changes in their frequency were evaluated by flow cytometry. Transcriptome analysis of circulating CX3CR1+ monocytes was also performed. Results DcR‐6 deficiency and CCL2 overexpression were observed in inflamed tissues from AS patients. In the gut, the proinflammatory CX3CR1+CD59+ MNP population was expanded, correlated with the presence of bacteria, and produced high levels of tumor necrosis factor–like molecule 1A (TL1A) and interleukin‐23 (IL‐23). MNPs positive for CD11b, CD11c, and major histocompatibility complex class II, predominantly expressing CX3CR1, were also expanded in the small intestines of treatment‐naive SKG relative to BALB/c mice. The frequency of gut‐derived CX3CR1+CD59+CCR9+TL1A+IL‐23+ MNPs was significantly higher in the peripheral blood and synovial fluid of AS patients than controls. CCR9+CX3CR1+CD59+ monocytes were also expanded in AS synovial and bone marrow samples. Transcriptome analysis of isolated CX3CR1+CD59+ monocytes demonstrated a specific proinflammatory profile in AS. Isolated proinflammatory CX3CR1+CD59+ MNPs from AS patients induced the expansion and activation of ILC3. Conclusion Proinflammatory CX3CR1+CD59+TL1A+IL‐23+ MNPs are expanded in AS patients and display a specific proinflammatory transcriptome profile. Given the ability of these cells to support ILC3 expansion, they may promote a sustained proinflammatory status in AS.

The balance of power: innate lymphoid cells in tissue inflammation and repair

“…The intestinal microenvironment and microbiota may enable the gut to serve as a portal for this transition. Intestinal biopsies from patients with IBD-associated ankylosing spondylitis showed an expansion of T-BET + ILC3s (132), and the expansion of TL1A-producing CX3CR1 + MNPs promoted T-BET + ILC3 activation in the synovial tissue (133). A parallel population of ex-ILC3s are also enriched in the synovial fluid of patients with psoriatic arthritis.…”

Gut-derived CD8+ tissue-resident memory T cells are expanded in the peripheral blood and synovia of SpA patients

“…The existence of a gut–joint has been hypothesised in SpA patients 3. The inflamed gut could actively participate in the pathogenesis of SpA through the production of proinflammatory cytokines, such as IL-23p194 and IL-9,5 and the differentiation of potentially pathogenic innate cells producing IL-22 and IL-17 3. T RM are a critical component of mucosal immune defence by acting as peripheral sentinels capable of rapidly mobilising protective tissue immunity on pathogen recognition 2.…”

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

“…CD163 + macrophages are expanded in SpA synovial tissue 162 and subchondral bone 161 , where they express IL-23. Histologically, CD68 + and CD163 + macrophages are enriched in gut tissue from patients with Crohn's disease and in patients with AS who have chronic gut inflammation 163 , but CD14 + myeloid cells are expanded only in those with Crohn's disease 164,165 . A 2018 study used flow cytometry to identify a unique population of CX3CR1 + CD59 + myeloid cells that was expanded in the gut of patients with AS; these IL-23-producing cells were capable of driving ILC3 expansion, and their presence correlated with bacterial infiltration into the epithelia 165 .…”