Background Tertiary lymphoid structures (TLS) are a hallmark of various autoimmune diseases. Phenotypical and functional changes associated with the acquisition of lymphoid-like features have been described in the stroma during TLS and cancer and suggested to drive formation and maintenance of the pathological lesions. To date the mechanisms responsible for the regulation of these changes are not known. IL-4R signalling has been recently described to regulate mesenchyme differentiation in muscle or adipose tissue injury and we hypothesise that the same signalling might play a role in regulating transition of normal resident mesenchyme stromal cells towards a lymphoid like/pathological phenotype.
Methods To test our hypothesis we used an inducible mouse model of TLS formation by retrograde cannulation of the salivary glands with a replication deficient adenovirus, able to induce TLS similar to those observed in Sjogren’s syndrome and Rheumatoid arthritis. Salivary glands of C57BL/6 mice wild type and knockout mice (IL-4Ra, IL-4, IL-13) were cannulated and sacrificed at different time points post cannulation (p.c.). Immunofluorescence, flow cytometry and RT-PCR were used to evaluate the dynamic of acquisition of lymphoid features and stromal cell activation.
Results In our mouse model of TLS formation, we demonstrated that in absence of IL-4R mediated signalling (IL-4R-/- mice) stromal cell activation does not occur and absence of lymphoid stromal cell markers is associated with abrogated chemokine expression and defective TLS formation. Similar phenotype was observed in IL-13-/- mice but not IL-4-/- mice where normal induction of TLS occurs. Investigation of IL-13GFP and IL-4GFP reporter mice as well as WT mice showed a high level of IL-13 but not IL-4 expression in the salivary gland at early time-points after TLS induction, thus suggesting that IL-13 more than IL-4 is responsible for stromal cell transition to a lymphoid phenotype. Interestingly, investigation of bone-marrow chimeric mice showed that the source of IL-13 was not only haematopoietic cells but both epithelial cells and other stromal cells were chiefly responsible for producing IL-13 in response to adenovirus infection. Interestingly, administration of recombinant IL-13 in absence of virus was sufficient to cause stromal cell activation in absence of viral insult.
Conclusions All together these results suggest that activation of quiescent tissue-resident stromal cells is mediated by engagement of IL4-R on resident stroma and strongly suggests the need for therapeutic approach aimed towards stroma to achieve disease control. Therapeutic intervention aimed to block this signalling in autoimmune conditions is currently under development.
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