Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity.
Eosinophils are frequently found in increased numbers in a variety of chronic fibrotic diseases; however, their role in the development of hepatic fibrosis has not been dissected in vivo. Here, we used interleukin-5 (IL-5) knockout (KO) mice to determine whether eosinophils contribute to the progressive liver fibrosis that develops in response to chronic Schistosoma mansoni infection. Although infection intensities were similar in C57BL/6 and IL-5 KO mice, the average size of granulomas was significantly smaller in both acutely and chronically infected IL-5 KO mice. Their granulomas were also completely devoid of eosinophils. In addition, the knockout mice displayed over a 40% reduction in hepatic fibrosis by week 16 postinfection. The reduced fibrosis was associated with increased production of the antifibrotic cytokine gamma interferon. Moreover, although IL-13 production did not decrease consistently in the absence of IL-5, IL-13-triggered responses were substantially reduced in the granulomatous tissues. This was confirmed by analyzing the expression of several genes associated with alternative macrophage activation, including arginase 1, Fizz-1, and YM-1. Importantly, all of these IL-13-regulated genes have been linked with the mechanisms of wound healing and fibrosis. In addition to IL-5 polarizing the antigen-specific CD4+ Th2 cell response, we found that granuloma eosinophils were themselves a significant source of IL-13. Thus, by producing profibrotic mediators and polarizing the Th2 response, these findings illustrate both direct and indirect roles for eosinophils and IL-5 in the pathogenesis of schistosomiasis-induced liver fibrosis. Thus, inhibiting the activity of IL-5 or eosinophils may prove effective for a variety of chronic fibrotic diseases.
Immunopathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-8003, USA.
Rachael M
RM
Reiman
Robert W
RW
Thompson
Carl G
CG
Feng
Danielle
D
Hari
Rachel
R
Knight
Allen W
AW
Cheever
Helene F
HF
Rosenberg
Thomas A
TA
Wynn
D000818:Animals; D018450:Disease Progression; D004804:Eosinophils / Q000473:pathology*; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015848:Interleukin-5 / Q000172:deficiency / Q000502:physiology*; D008103:Liver Cirrhosis / Q000473:pathology*; D008109:Liver Diseases, Parasitic / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D018793:Interleukin-13; D015848:Interleukin-5