Matrix Metalloproteinase 12-Deficiency Augments Extracellular Matrix Degrading Metalloproteinases and Attenuates IL-13–Dependent Fibrosis

Abstract

Infection with the parasitic helminth Schistosoma mansoni causes significant liver fibrosis and extracellular matrix (ECM) remodeling. Matrix metalloproteinases (MMP) are important regulators of the ECM by regulating cellular inflammation, extracellular matrix deposition, and tissue reorganization. MMP12 is a macrophage-secreted elastase that is highly induced in the liver and lung in response to S. mansoni eggs, confirmed by both DNA microarray and real-time PCR analysis. However, the function of MMP12 in chronic helminth-induced inflammation and fibrosis is unclear. In this study, we reveal that MMP12 acts as a potent inducer of inflammation and fibrosis after infection with the helminth parasite S. mansoni. Surprisingly, the reduction in liver and lung fibrosis in MMP12-deficient mice was not associated with significant changes in cytokine, chemokine, TGF-β1, or tissue inhibitors of matrix metalloproteinase expression. Instead, we observed marked increases in MMP2 and MMP13 expression, suggesting that Mmp12 was promoting fibrosis by limiting the expression of specific ECM-degrading MMPs. Interestingly, like MMP12, MMP13 expression was highly dependent on IL-13 and type II–IL-4 receptor signaling. However, in contrast to MMP12, expression of MMP13 was significantly suppressed by the endogenous IL-13 decoy receptor, IL-13Rα2. In the absence of MMP12, expression of IL-13Rα2 was significantly reduced, providing a possible explanation for the increased IL-13-driven MMP13 activity and reduced fibrosis. As such, these data suggest important counter-regulatory roles between MMP12 and ECM-degrading enzymes like MMP2, MMP9, and MMP13 in Th2 cytokine-driven fibrosis.

Th2 Cytokines Augment IL-31/IL-31RA Interactions via STAT6-dependent IL-31RA Expression

“…Mice were sacrificed 24 h after the final airway challenge (day 32), and lungs were collected in RNAlater solution (Applied Biosystems TM , Life Technologies TM , ThermoFisher Scientific) and stored at Ϫ80 ºC until use. RNA Isolation, cDNA Synthesis, and Quantitative PCR-RNA was isolated using the RNeasy kit (Qiagen Sciences, Valencia, CA) as described previously (21). A total of 1 g of RNA was used for cDNA synthesis, and gene expression was measured using the StepOnePlus TM sequence detection system (Applied Biosystems).…”

“…However, mice deficient for IL-13R␣1 showed no significant increase in IL-31RA expression compared with wild-type mice during SEA-induced allergic asthma. One possible explanation for no increase in IL-31RA transcripts in IL-13R␣ Ϫ/Ϫ mice could be in vivo dependence of IL-13 to induce the pathophysiological features of asthma (21,25,27,28). In support, the absence of IL-13R␣2, a decoy receptor of IL-13 has resulted in a further increase in IL-31RA expression compared with wild-type mice during SEA-induced allergic asthma.…”

“…To determine the role of different Th2 cytokine receptors in IL-31RA expression, macrophages were treated with IL-4 or IL-13 in the presence or absence of neutralizing antibodies to IL-4R␣ or IL-2R␥C that can selectively block signaling receptors for IL-4 and IL-13 (21). IL-4, but not IL-13 signals via the Type I IL-4 receptor, which is a heterodimeric complex com- Ϫ/Ϫ macrophages were cultured with IL-4 (20 ng/ml) and IL-13 (20 ng/ml), and mRNA level of IL-31RA expression was measured.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Global gene analysis reveal that MMP-12 is highly induced in the liver and lung in response to S. mansoni eggs (Sandler et al, 2003); therefore, a role of MMP-12 in the chronic helminth-induced inflammation and fibrosis has been postulated. In their study Satish and co-workers, using MMP-12-deficient mice, observe that MMP-12 promotes inflammation and Th2 cytokine-driven fibrosis in schistosomiasis by limiting the expression of ECM-degrading MMPs, such as MMP-2 and MMP-13 (Madala et al, 2010).…”

Contribution of myeloid cell subsets to liver fibrosis in parasite infection

“…IFNγ also regulates the Th17 response and thereby favours the transition from an acute to a chronic infection [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. Yet, at this stage, despite granuloma involution as eggs are killed and the development of hyporesponsiveness in Th2 cells [47], the Th2/M2 inflammatory response elicits tissue remodelling, including induction of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and collagens, that culminates in life-threatening liver and intestinal fibrosis, portal hypertension and haemorrhages (16-20 wkpi) [28,38,41,[48][49][50]. IL-13, via the IL-13Rα1/IL-4Rα receptor, is the most important fibrotic agent in schistosomiasis, with additive effects of IL-4, IL-5, IL-10 and IL-21 but not of TGFβ [45,[50][51][52][53].…”