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Polycystic liver disease is suppressed by IL-4/IL-13 and TGF-beta signaling

Thursday, September 17, 2015 — Poster Session III

3:30 p.m. – 5:00 p.m.
FAES Terrace
NIAID
IMMUNO-5

* FARE Award Winner

Authors

  • DA Cantu
  • K Kindrachuk
  • L Borthwick
  • D Donahue
  • D Morris
  • D Dorwood
  • B Klaunberg
  • T Ramalingam
  • S White
  • R Thompson
  • TA Wynn

Abstract

Polycystic liver disease (PLD) is a relatively rare but devastating condition that causes cysts to grow throughout the liver. The immunological mechanisms controlling liver cyst formation, however, remain unclear. In this study, we show that during infection with the helminth parasite Schistosoma mansoni, severe PLD-like disease develops when infected mice are deficient in both IL-4 and IL-13, suggesting that Stat6-mediated signaling is critically required to prevent the development of PLD. We hypothesized that the parasite eggs might be contributing to cyst formation by promoting damage to microvessels in the liver, which are not efficiently repaired when mice are deficient in both IL-4 and IL-13. IL-4 and IL-13 are linked with wound repair and are potent inducers of transforming growth factor-beta (TGF-b) expression. We examined whether cyst formation in IL-4/IL-13-deficient mice was linked with uncontrolled type 1-associated inflammation and maladaptive repair. Histological analysis of liver tissues from IL-4/IL-13 dKO mice revealed an elevated infiltration of F4/80+ macrophages that co-localized with TGF-b-inducible protein along the cyst border, suggesting TGF-b signaling was elevated in the dKO mice. To elucidate the role of TGF-b, infected IL-4/IL-13 dKO mice were treated with a pan neutralizing TGF-b monoclonal antibody (mAb). The number and size of cysts was dramatically increased when type-2 cytokines and TGF-b signaling were simultaneously blocked, suggesting that IL-4, IL-13, and TGF-b collaborate to prevent PLD during chronic S. mansoni infection. These studies suggest that therapeutic strategies that increase IL-4/IL-13 and TGF-b signaling might provide a rational approach to treat patients with progressive PLD.

Category: Immunology