The protective and pathogenic roles of IL-17 in viral infections: friend or foe?

Abstract

Viral infections cause substantial human morbidity and mortality, and are a significant health burden worldwide. Following a viral infection, the host may initiate complex antiviral immune responses to antagonize viral invasion and replication. However, proinflammatory antiviral immune responses pose a great threat to the host if not properly held in check. Interleukin (IL)-17 is a pleiotropic cytokine participating in a variety of physiological and pathophysiological conditions, including tissue integrity maintenance, cancer progression, autoimmune disease development and, more intriguingly, infectious diseases. Abundant evidence suggests that while IL-17 plays a crucial role in enhancing effective antiviral immune responses, it may also promote and exacerbate virus-induced illnesses. Accumulated experimental and clinical evidence has broadened our understanding of the seemingly paradoxical role of IL-17 in viral infections and suggests that IL-17-targeted immunotherapy may be a promising therapeutic option. Herein, we summarize current knowledge regarding the protective and pathogenic roles of IL-17 in viral infections, with emphasis on underlying mechanisms. The various and critical roles of IL-17 in viral infections necessitate the development of therapeutic strategies that are uniquely tailored to both the infectious agent and the infection environment.

Keywords: IL-17; antiviral immunity; immunopathogenesis; inflammation; viral infections.

Figure 1.

IL-17 can enhance antiviral B-cell activities and promote the survival of virus-infected cells during influenza virus infection. Upon influenza virus infection, (a) IL-17 induces the secretion of CXCL13 from necrotic lung epithelial cells. CXCL13 is a potent chemoattractant for CXCR5⁺ B cells, which migrate into the lung and produce abundant neutralizing antibodies to suppress influenza virus infection. In addition, IL-17 can induce Blimp-1 expression and NF-κB activation in B1a cells, resulting in natural IgM antibody production and the suppression of viral infection. (b) γδT-cell-derived IL-17 stimulates IL-33 secretion by necrotic lung epithelial cells. IL-33 facilitates the induction and infiltration of ILC2s and Tregs, which secrete amphiregulin to promote the growth of lung epithelial cells. CXCL13, CXC-chemokine ligand 13; CXC-chemokine receptor 5; Treg, regulatory T cell; ILC2, type 2 innate lymphoid cell.

Figure 2.

IL-17 promotes the progression of liver fibrosis during HBV infection. During HBV infection, virus-infected hepatocytes release TSLP, which stimulates the production of Th17 differentiation-associated cytokines (i.e. TGF-β, IL-6 and IL-21) from hepatic DCs, leading to the differentiation of naive CD4⁺ T cells into IL-17-producing Th17 cells. In addition, virus-activated DCs also stimulate the generation of Th17 cells by producing IL-23. The production of IL-17 activates HSCs, the major ECM-producing cells in the liver. Excessive ECM degradation leads to liver fibrosis and hepatocyte apoptosis observed in these patients. TGF-β, transforming growth factor-β; DC, dendritic cell; TSLP, thymic stromal lymphopoietin; HSC, hepatic stellate cell; HBV, hepatitis B virus; ECM, extracellular matrix.