The IL-33/ST2 pathway controls coxsackievirus B5-induced experimental pancreatitis

• Published in: The Journal of immunology (1950) Vol. 191; no. 1; pp. 283 - 292
• Main Authors: Sesti-Costa, Renata, Silva, Grace K, Proença-Módena, José L, Carlos, Daniela, Silva, Maria L, Alves-Filho, José C, Arruda, Eurico, Liew, Foo Y, Silva, João S
• Format: Journal Article
• Language: English
• Published: United States 01.07.2013
• Subjects: Animals; Cells, Cultured; Coxsackievirus; Coxsackievirus Infections - immunology; Coxsackievirus Infections - metabolism; Coxsackievirus Infections - pathology; Disease Models, Animal; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Interleukins - administration & dosage; Interleukins - biosynthesis; Interleukins - physiology; Mice; Mice, Inbred BALB C; Mice, Knockout; Pancreatitis - immunology; Pancreatitis - pathology; Pancreatitis - virology; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - physiology; Signal Transduction - immunology; Viral Load - immunology; Weight Loss - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202806

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.