A role for neutrophils in early enthesitis in spondyloarthritis

Abstract

Background Neutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of neutrophils in the experimental SKG mouse model of SpA and in human axial entheses. Methods Early inflammatory infiltrates in the axial and peripheral entheseal sites in SKG mice were evaluated using immunohistochemistry and laser capture microdissection of entheseal tissue. Whole transcriptome analysis was carried out using Affymetrix gene array MTA 1.0, and data was analyzed via IPA. We further isolated neutrophils from human peri-entheseal bone and fibroblasts from entheseal soft tissue obtained from the axial skeleton of healthy patients and determined the response of these cells to fungal adjuvant. Results Following fungal adjuvant administration, early axial and peripheral inflammation in SKG mice was characterized by prominent neutrophilic entheseal inflammation. Expression of transcripts arising from neutrophils include abundant mRNA for the alarmins S100A8 and S100A9. In normal human axial entheses, neutrophils were present in the peri-entheseal bone. Upon fungal stimulation in vitro, human neutrophils produced IL-23 protein, while isolated human entheseal fibroblasts produced chemokines, including IL-8, important in the recruitment of neutrophils. Conclusion Neutrophils with inducible IL-23 production are present in uninflamed human entheseal sites, and neutrophils are prominent in early murine spondyloarthritis-related enthesitis. We propose a role for neutrophils in the early development of enthesitis.

Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease

“…Although the amount of the MIF secretion after stimulation with LPS or curdlan was not altered in SpA neutrophils relative to control neutrophils, the higher baseline expression of MIF in SpA patients demonstrated the chronic activation of circulating neutrophils in SpA, potentially triggered by underlying inflammation in the joint, gut, skin, and eyes. In addition to our data, neutrophils have recently been identified in human spinal entheses and produce IL-23 upon stimulation with fungal components ( 37 ). Our RNA-seq followed by validation with immunoblotting analysis determined that DTL, a negative regulator of IL-23, is up-regulated in Mif KO neutrophils compared to WT neutrophils, suggesting that MIF down-regulates the expression of DTL regulating the expression of IL-23 in neutrophils.…”

The Role of Neutrophils in Spondyloarthritis: A Journey across the Spectrum of Disease Manifestations

“…To conclude, a clue for neutrophil involvement in uveitis related to SpA can be inferred from anatomical studies, as McGonagle and colleagues proposed that the connective tissue of uveal structures, especially at the level of ciliary body tendons attachment, may be considered as a classical musculoskeletal enthesis. The same group, as mentioned above, recently described the presence of neutrophils at entheses so that we can speculate a possible common immunologic milieu for skeleton and eye structures, both contributing to SpA manifestations [ 24 ].…”

“…The presence and activation of neutrophils, together with a marked increase in the alarmins S100A8 and S100A9, were elegantly showed by Stavre Z. in SKG mice withcurdlan-indiced enthesitis, a common use animal model for chronic arthritis [ 23 , 24 ]. These aforementioned alarmins constitute calprotectin, a biomarker of inflammation for both SpA and IBD, in close relationship with the development of tendinopathy, SpA structural damage, psoriasis, and gut inflammation [ 25 , 26 , 27 ].…”

Hyaluronic Acid in Synovial Fluid Prevents Neutrophil Activation in Spondyloarthritis

“…To do so, they are equipped with various effector functions such as degranulation, mediator release, reactive oxygen species (ROS) production, phagocytosis, and neutrophil extracellular trap (NET) formation [ 10 , 11 ]. However, neutrophils are also associated with various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD) [ 12 , 13 , 14 ]. In IBD, a disease closely related to SpA, disease severity correlates with the number of invasive neutrophils [ 12 ].…”