Matrix metalloproteinase 28 is regulated by TRIF- and type I IFN-dependent signaling in macrophages

Matrix metalloproteinases (MMPs) are transcriptionally regulated proteases that have multiple roles in modifying the extracellular matrix (ECM) and inflammatory response. Our previous work identified Mmp28 as a key regulator of inflammation and macrophage polarization during experimental models of pulmonary infection, fibrosis, and chronic smoke exposure. However, the signaling pathways responsible for regulation of macrophage Mmp28 expression remain undefined. This study utilized murine macrophages obtained from wild type, Tlr2(−/−), Tlr4(−/−), MyD88(−/−), Ticam1(Lps2) (Trif(mutant)), and Ifnar1(−/−) mice to test the hypothesis that macrophage Mmp28 expression was dependent on TRIF and type I IFN. Our results support the hypothesis, demonstrating that increased macrophage Mmp28 expression was dependent on type I IFN after LPS and poly(I:C) stimulation. To gain further insight into the function of MMP28, we explored the inflammatory response of macrophages derived from wild type or Mmp28(−/−) mice to stimulation with poly(I:C). Our data support a role for MMP28 in regulating the macrophage inflammatory response to poly(I:C) because expression of Ccl2, Ccl4, Cxcl10, and Il6 were increased in Mmp28(−/−) macrophages. Together, these data support a model in which macrophages integrate TRIF- and type I IFN-dependent signaling to coordinate regulation of proteins with the capacity to modify the ECM.