Model of MMP regulation of chemokine action and inflammation.

(A) In response to host challenge, cytokines are released, and a chemotactic gradient is bound in the matrix to attract leukocytes from the vasculature. (B) Infiltration requires matrix proteolysis, predominantly by leukocyte-derived MMP-8 and MMP-9. As the cellular infiltrate builds, growth factors and cytokines are released by infiltrating cells and induced stromal cells. Stromal cells respond to autocrine and paracrine cytokine stimulation by increasing MMP expression. (C) In addition to clearance of matrix protein fragments, MMP activity converts MCP chemoattractants to CCR-1, CCR-2, and CCR-3 antagonistic derivatives, which both disrupt retention and reduce recruitment of the cellular components of the inflammatory infiltrate. With time, general MMP expression is suppressed, concomitant with increased MMP-2 and TIMP levels under the influence of transforming growth factor–β1 (TGF-β1), which orchestrates the final remodeling of the extracellular matrix.