Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling

Background:  Activation of innate immunity through polyinosinic:polycytidylic acid [poly(I:C)] causes acute salivary gland hypofunction. As a major consequence of poly(I:C) treatment is type I interferon (IFN) production, this study was undertaken to investigate their role in salivary gland dysfunction. Methods:  Different strains of mice deficient in either interferon alpha receptor (IFNAR1 −/− ) or IL‐6 −/− , or IL‐10 −/− , or EBI3 −/− were treated with poly(I:C). Salivary gland function was determined by measuring pilocarpine‐induced saliva volume. Gene expression levels were measured by real‐time PCR. Ca 2+ mobilization studies were performed using ex‐vivo acinar cells. Results:  A single injection of poly(I:C) rapidly induced salivary gland hypofunction in wild‐type B6 mice (41% drop in saliva volumes compared to PBS‐treated mice). In contrast, the loss of function in poly(I:C)‐treated IFNAR −/− mice was only 9.6%. Gene expression analysis showed reduced levels of Il‐6, Il‐10, and Il‐27 in submandibular glands of poly(I:C)‐treated IFNAR −/− mice. While salivary gland dysfunction in poly(I:C)‐treated IL‐10 −/− and EBI3 −/− mice was comparable to wild‐type mice, the IL‐6 −/− mice were more resistant, with only a 21% drop in function. Pilocarpine‐induced Ca 2+ flux was significantly suppressed in acinar cells obtained from poly(I:C)‐treated wild‐type mice. Conclusions:  Our data demonstrate that a combined action of type I IFNs and IL‐6 contributes toward salivary gland hypofunction. This happens through interference with Ca 2+ mobilization within acinar cells. Thus, in acute viral infections and diseases like Sjögren’s syndrome, elevated levels of type I IFNs and IL‐6 can directly affect glandular function.