Background: Interleukin 7 (IL-7) plays a key role in T cell biology and its effects are modulated by the pro-inflammatory soluble form of the receptor (IL7R). Polymorphisms of IL7R are associated with multiple inflammatory diseases including multiple sclerosis and ankylosing spondylitis and the disease-associated variant leads to increased circulating soluble IL7R (sIL7R). IL7R mRNA is induced in stimulated monocytes in a genetically determined manner, yet a role for IL7R in monocyte biology remains unexplored.
Methods: Monocyte surface IL7R protein was measured by flow cytometry after LPS stimulation in a cohort of genotyped volunteers(n=84). sIL7R was quantified by ELISA in purified monocyte cultures stimulated with LPS from separate cohort (n=161) of genotyped donors. Bulk and single-cell RNA sequencing was performed on in-vitro stimulated monocytes and synovial monocytes of patients with spondyloarthritis.
Results: Monocyte surface and soluble IL7R protein are markedly expressed in response to LPS and stimulated monocytes are the main cellular source of sIL7R. Alleles of rs6897932 are the key determinant of both surface IL7R and sIL7R in stimulated monocytes. Stimulated monocytes were sensitive to exogenous IL-7, which elicits a defined transcriptional signature. Single-cell RNA sequencing of synovial fluid monocytes from patients with spondyloarthritis showed an distinct subset of IL7R+ monocytes with a unique transcriptional profile that markedly overlapped the in-vitro IL-7 induced geneset.
Conclusions: These data demonstrate disease-associated genetic variants at IL7R specifically impact monocyte surface IL7R and sIL7R following innate immune stimulation, suggesting a previously unappreciated key role for monocytes in IL-7 pathway biology and IL7R-associated diseases.