Abstract
Using an in vivo model of tolerance to TLR7-induced skin inflammation, we found a critical role for macrophage-derived MMP10 in mediating immune hypo-responsiveness. Cutaneous exposure to Imiquimod (IMQ), a TLR7 agonist, induced acute expression of pro-inflammatory factors (IL1β, IL6, CXCL1) and neutrophil influx equally in both wildtype and Mmp10−/− mice. However, whereas subsequent exposure (11 and 12 days later) to IMQ led to marked abrogation of pro-inflammatory factor expression in wildtype mice, Mmp10−/− mice responded similarly as they did to the first application. In addition, the second exposure led to increased expression of negative regulators of TLR signaling (TNFAIP3, IRAK3) and immunosuppressive cytokines (IL10, TGFβ1) in wildtype mice but not in Mmp10−/− mice. In vitro studies demonstrated that prior exposure of IMQ to bone marrow-derived macrophages (BMDM) made wildtype cells refractory to subsequent stimulation but did not for Mmp10−/− macrophages. These findings expand the critical roles MMP10 plays in controlling macrophage activation to indicate that the development of immune tolerance to TLR7 ligand is dependent on this macrophage-derived proteinase.
Highlights
Toll-like receptors (TLRs) are a family of highly conserved Pattern Recognition Receptors that are activated by pathogen-associated and damage-associated molecular patterns
We reported that stromelysin-2 (MMP-10), which is expressed by macrophages, promotes the activation of immunosuppressive and matrix-degrading programs in macrophages, including resident skin macrophages [12,13,14]
As macrophages are involved in immune tolerance [19, 20], including tolerance to TLR7 ligands [21, 22], we explored if MMP10 impacts macrophage responses to TLR7 activation
Summary
Toll-like receptors (TLRs) are a family of highly conserved Pattern Recognition Receptors that are activated by pathogen-associated and damage-associated molecular patterns. TLRs affect macrophage activation typically by promoting their polarization toward pro-inflammatory states [15]. Our findings demonstrate that prior topical treatment with Imiquimod (IMQ), a TLR7 agonist, dampened proinflammatory responses, and promoted tolerance to subsequent application of IMQ at a different site. Using both in vivo and cell-based approaches, we found that these effects were dependent on MMP10 in macrophages. These observations expand the roles for MMP10 in being a critical effector of macrophage activation
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