Interleukin-4 (IL-4) and IL-13 Suppress Excessive Neutrophil Infiltration and Hepatocyte Damage during Acute Murine Schistosomiasis Japonica

Abstract

Due to the importance of neutrophils and proinflammatory cytokines in schistosomal liver damage, we analyzed the mechanisms underlying neutrophil and proinflammatory responses in murine schistosomiasis japonica. We found that granulomatous inflammation around parasite eggs in the liver was greater in Schistosoma japonicum-infected IL-4 ؊/؊ IL-13 ؊/؊ (doubleknockout [DKO]) mice than in infected wild-type (WT) mice at 6 weeks, but not at 8 weeks, postinfection, suggesting the importance of Th2 responses in these typical hepatic lesions. Infected DKO mice also showed increased neutrophil infiltration accompanying more severe pathology, as shown by the enhanced necrosis of hepatocytes. This was not likely due to a Th1/Th2 imbalance, because there was no detectable increase in gamma interferon (IFN-␥) production in these DKO mice. mRNA expression of interleukin-17A (IL-17A), proinflammatory cytokines, and the neutrophil chemoattractant CXCL2 in liver was higher in infected DKO mice than in WT mice. However, in IL-4 ؊/؊ IL-13 ؊/؊ IL-17A ؊/؊ (triple-knockout [TKO]) mice, the absence of IL-17A was associated with only marginal differences in schistosomal liver damage, suggesting that IL-17A is only partially responsible for neutrophil-driven hepatic damage. Furthermore, the expression of mRNAs encoding proinflammatory cytokines was not under the control of IL-17A in TKO mice. These findings indicate that IL-4 and IL-13 suppress excessive neutrophil recruitment, proinflammatory cytokine production, and hepatic damage during the acute stage of S. japonicum infection, suggesting that neutrophils and proinflammatory cytokines are mainly responsible for hepatocyte damage during acute murine schistosomiasis japonica. However, neutrophil induction and the production of proinflammatory cytokines were not due solely to IL-17A.

Coinfection with an Intestinal Helminth Impairs Host Innate Immunity against Salmonella enterica Serovar Typhimurium and Exacerbates Intestinal Inflammation in Mice

“…It was found that during the early phase of Pseudomonas aeruginosa infection, neutrophil recruitment and cytokine (TNF-␣) and chemokine (KC) expres- sion were significantly decreased in the IL-10 transgenic mice, which resulted in impaired clearance of P. aeruginosa (32). It has been shown previously that IL-10 reduces the stability of a number of mRNAs, including KC, TNF-␣, and MIP-1 (33,34). The molecular events responsible for IL-10-mediated downregulation of MIP2 are less clear.…”

NKT Deficient Mice are not Spared Lung Disease after Exposure to Thoracic Radiotherapy

“…Given that neutrophil chemotaxis is dictated by the cytokines present in the lung, it is possible that the lower PMN numbers observed in Ja18 -/-males are due to a different cytokine environment compared to C57BL/6J mice. For example NKT cell products Il13 and Il4 (13) can reduce neutrophilia (31), possibly by inhibiting production of neutrophil chemoattractant, Il17 (32), but are both potent pro-fibrotic mediators (33,34). Thus, a higher concentration of these cytokines in Ja18 -/-mice could trigger a fibrotic response in the absence of neutrophilia.…”

Contribution of myeloid cell subsets to liver fibrosis in parasite infection

“…Although IL-4/IL-13 signalling suppressed the excess of neutrophil accumulation in both schistosome infections, acute hepatic granuloma inflammation in mice lacking IL-4/IL-13 signalling was impaired in mansoni schistosomiasis, while being more severe in japonicum schistosomiasis, suggesting that a moderate neutrophil infiltration is required to limit the hepatic lesion in acute S. japonicum-infected mice [126]. In addition, unlike in S. mansoni infection, the mortality rate of infected mice did not increase in the absence of IL-4/ IL-13 [32,33,126,135]. Whether the Th17/neutrophil response contributes to prolonged survival and influences the development of fibrosis in S. japonicuminfected mice deserves investigation.…”

“…In contrast to skin macrophages and similar to skin eosinophils, skin neutrophils did not exert a suppressive activity on the capacity of DCs to trigger T cell proliferation [65,66]. However, in models where IL-17 was associated with the pathogenicity of schistosomiasis, Th17 responses driven by an IL-23p19/IL-1β pathway favoured neutrophil recruitment/accumulation and degranulation, thereby exacerbating egg-induced tissue damage and causing mortality in acute infection [35,40,42,[123][124][125][126][127]. Considering the death in acute infection of mice developing IL-17-mediated pathogenicity, the contribution of neutrophils to fibrosis was not clearly addressed.…”

“…Although the basic immune mechanisms associated with the development of granuloma and fibrosis are similar in S. mansoni and S. japonicum infection [21][22][23], more severe hepatic lesions and more vigorous Th17/IL-17-dependent neutrophil hepatic granulomatous inflammation developed in S. japonicum acute infection [123,127,134]. Although IL-4/IL-13 signalling suppressed the excess of neutrophil accumulation in both schistosome infections, acute hepatic granuloma inflammation in mice lacking IL-4/IL-13 signalling was impaired in mansoni schistosomiasis, while being more severe in japonicum schistosomiasis, suggesting that a moderate neutrophil infiltration is required to limit the hepatic lesion in acute S. japonicum-infected mice [126]. In addition, unlike in S. mansoni infection, the mortality rate of infected mice did not increase in the absence of IL-4/ IL-13 [32,33,126,135].…”