Matrix metalloproteinase 12 (MMP12), a protease involved in macrophage migration, could also have a crucial role in regulating the resolution of inflammation. The results of a new study indicate that MMP12 cleaves IFNγ, thereby rendering the cytokine unable to signal via its receptor.

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In this study, the researchers investigated interactions between MMP12 and IFNγ in vitro before using Mmp12+/+ and Mmp12–/– mice with acute peritonitis to monitor the effects of these interactions in vivo.

MMP12 cleaves IFNγ, thereby rendering the cytokine unable to signal via its receptor

“We found that MMP12 efficiently inactivates IFNγ by two C-terminal cleavages that remove the IFNγ receptor-binding site. These cleavages halt downstream signalling and classical-activation to M1 (IFNγ-activated) macrophages,” explains corresponding author Christopher Overall. “Moreover, we found that M2 (IL-4-activated) macrophages express >3-fold more MMP12 than the pro-inflammatory M1 macrophages. This suggests a new feedback inhibition mechanism executed by M2 cells that reduces the ratio of destructive M1 cells and so favours M2 cells and disease resolution.”

Interestingly, the results from mice with peritonitis were mirrored in the MRL/lpr mouse model of systemic lupus erythematosus (SLE); IFNγ signalling was prolonged in Mmp12–/– mice compared with Mmp12+/+ mice and supported a sustained pro-inflammatory response.

Re-analysis of previously published transcriptome datasets revealed an inverse correlation between MMP12 mRNA and mRNA of IFNγ-response genes in patients with SLE that was not present in healthy individuals. Over time, this inverse correlation was associated with increased disease activity, but was reversed in patients who responded well to therapy. Furthermore, levels of MMP12-cleaved IFNγ were lower in tissue samples from the kidneys of patients with lupus nephritis than in those from healthy individuals.

“Macrophage activation patterns remain under-explored in autoimmune diseases, as does the post-translational regulation of cytokines. Genetic analyses alone will miss the important contribution made by proteolytic processing of cytokines,” concludes Overall.