Macrophage MMP10 Regulates TLR7-Mediated Tolerance

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Toll-like receptor 7 (TLR7) agonists like Imiquimod (IMQ) induce skin inflammation.
• Immune tolerance, a state of hypo-responsiveness, can develop after repeated exposure to inflammatory stimuli.

Purpose of the Study:

• To investigate the role of matrix metalloproteinase-10 (MMP10) in the development of immune tolerance to TLR7-induced skin inflammation.

Main Methods:

• Utilized an *in vivo* mouse model of TLR7-induced skin inflammation.
• Compared wildtype and *Mmp10* knockout mice ( *Mmp10*^-/-).
• Assessed inflammatory factor expression, neutrophil influx, and regulatory molecule expression after single and repeated IMQ exposure.
• Conducted *in vitro* studies using bone marrow-derived macrophages (BMDM).

Main Results:

• Both wildtype and *Mmp10*^-/- mice showed similar acute inflammatory responses to the first IMQ exposure.
• Wildtype mice developed tolerance upon secondary IMQ exposure, characterized by abrogated pro-inflammatory factor expression.
• *Mmp10*^-/- mice failed to develop tolerance, responding similarly to the first IMQ application.
• Wildtype mice exhibited increased expression of negative TLR signaling regulators and immunosuppressive cytokines after secondary IMQ exposure, unlike *Mmp10*^-/- mice.
• *In vitro*, wildtype BMDMs became refractory to restimulation after initial IMQ exposure, while *Mmp10*^-/- BMDMs did not.

Conclusions:

• Macrophage-derived MMP10 is essential for mediating immune hypo-responsiveness to TLR7 ligands.
• The development of immune tolerance to TLR7 agonists is dependent on MMP10.
• MMP10 plays a critical role in regulating macrophage activation and controlling the development of immune tolerance.