The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Abstract

Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-γ and TNF-α are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-γ and TNF-α by CD8+ T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL-4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2−/− mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus-induced pancreatitis, which is a major medical condition with unmet clinical needs.

The conspiracy of autophagy, stress and inflammation in acute pancreatitis

“…Consistent with other pancreatitis models, coxsakievirus infection induces autophagy within the cells the virus infects [40]. Now we know that Salmonella infection is capable of direct invasion of pancreas cells and capable of inducing a pancreatitis response.…”

Crucial and Diverse Role of the Interleukin-33/ST2 Axis in Infectious Diseases

“…IL-33 also triggers the production of IL-4 by mast cells, leading to attenuation of inflammatory pancreatitis through alternative macrophage and T regulatory cell differentiation. These data further suggest a novel approach in treating virus-induced pancreatitis (35).…”

“…IL-33 expressed by keratinocytes infected with herpes simplex virus induces the expression of TNF-␣ and IL-6 in mast cells, leading to a protective immune response (34). Similar to other intracellular infections, the control of coxsackie B virus infection is associated with Th1 cells producing IFN-␥ and TNF-␣, but an exacerbated Th1 response may lead to injurious inflammatory lesions (35). In a model of mice treated with recombinant IL-33, IL-33 was shown to enhance the production of IFN-␥ and TNF-␣ by CD8 ϩ T and NK cells, which is associated with viral clearance (35).…”

“…Similar to other intracellular infections, the control of coxsackie B virus infection is associated with Th1 cells producing IFN-␥ and TNF-␣, but an exacerbated Th1 response may lead to injurious inflammatory lesions (35). In a model of mice treated with recombinant IL-33, IL-33 was shown to enhance the production of IFN-␥ and TNF-␣ by CD8 ϩ T and NK cells, which is associated with viral clearance (35). IL-33 also triggers the production of IL-4 by mast cells, leading to attenuation of inflammatory pancreatitis through alternative macrophage and T regulatory cell differentiation.…”

IL-33 Receptor ST2 Amplifies the Expansion of NK Cells and Enhances Host Defense during Mouse Cytomegalovirus Infection

“…ST2 is expressed on many immune cells (12, 15, 16), and the IL-33-ST2 signaling pathway augments IL-12-induced IFN-γ production by NK cells (15, 16). ST2 is essential for control of Coxsackievirus B5-induced pancreatitis by enhancing IFN-γ production by NK cells, which is associated with viral clearance (17). Here, we investigated the role of the IL-33-ST2 signaling axis in the adaptive immune response of NK cells during MCMV infection.…”