Background Bcl10 is a member of the CARMA3-Bcl10-MALT1 (CBM) signalosome that links angiotensin (Ang) II and NF-κB signaling. We have shown earlier that Ang II-infused Bcl10 knockout (KO) mice develop less inflammatory cell infiltration and less fibrosis coupled with improved arrhythmogenic electrical remodeling compared to wild-type (WT) littermates. In our present study we investigated the mechanism behind this phenotype.
Methods and Results Bone marrow (BM) from WT and green fluorescence protein transgenic WT mice (GFP+ WT) was transferred into WT and Bcl10 KO mice. Conversely, Bcl10 KO BM was transferred into WT mice. After BM regeneration mice were uni-nephrectomized, 1% NaCl was given in the drinking water and received Ang II (1.44 mg/kg/d) for 14 days. Both Bcl10 BM transplanted WT mice and WT BM transplanted Bcl10 KO mice showed less immune cell infiltration compared to WT BM transplanted WT mice (macrophages: 44.8±2.7 and 46.8±1.8 vs. 62.0±1.5; CD4+ T-cells: 22.8±1.4 and 24.3±1.3 vs. 31.2±0.9; CD8+ T cells 24.2±1.2 and 28.0±1.1 vs. 39.5±1.1 cells/heart section, respectively) despite similar cardiac hypertrophy. In parallel with cell infiltration these mice developed less perivascular collagen 1 and interstitial fibronectin deposition, as well. Immunohistological and qPCR analysis revealed less VCAM-1, ICAM-1 and chemokines (MCP-1 and RANTES) expression in WT BM transplanted Bcl10 KO mice compared to Bcl10 BM transplanted or WT BM transplanted WT mice. Moreover, in vitro endothelial cells transfected with Bcl10 siRNA showed 5-fold less increase in monocyte attachment after Ang II treatment as endothelial cells transfected with control siRNA. Additionally, transplantation with GFP+ WT BM cells revealed that Bcl10 KO mice recruit less BM-derived GFP+/FSP1+ fibroblasts compared to GFP+ WT BM transplanted WT mice (51.3±1.3 vs. 23.5± 1.3 cells/heart section) suggesting that non-cardiac cells contribute to fibrosis too. Finally, intraperitoneal injection of MCP-1 into WT mice significantly increased the number of peritoneal CD11b+ cells, whereas Bcl10 KO mice showed no increase in response to MCP-1.
Conclusion Our results demonstrate that cardiac fibrosis in Bcl10 KO mice depends on both immune/BM-derived cells and resident cardiac cells.