Matrix metalloproteinase–inhibitor imbalance in Kawasaki disease and multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) are pediatric hyperinflammatory conditions with overlapping features, but their molecular basis remains poorly defined. Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors of metalloproteinases (TIMPs), and inducers like EMMPRIN, are a tightly regulated proteolytic system that controls extracellular matrix ECM homeostasis and modulate immune responses. We profiled serum concentrations of MMPs, TIMPs, and related mediators (EMMPRIN and TNF-α) in 42 children with MIS-C, 5 with KD, 41 febrile controls, and 25 healthy controls. At presentation, MIS-C/KD showed a distinct protease–inhibitor signature characterized by markedly elevated TIMP-1, MMP-8, MMP-3, and TNF-α, with ratios indicating a net proteolytic bias despite compensatory TIMP upregulation. TIMP-1 and MMP-8 demonstrated excellent diagnostic performance (AUC >0.94 vs controls), and TIMP-1 correlated most strongly with clinical severity (ρ=0.55). Treatment with IVIG and corticosteroids reduced EMMPRIN but was paradoxically associated with rebound increases in MMP-1 activity. High-dose steroids blunted the post-treatment decline of neutrophil-derived proteases (MMP-8 and MMP-13). Subgroup analyses linked renal and cardiovascular involvement, shock, and gastrointestinal disease to the most pronounced biomarker alterations, driven by TIMP-1 and EMMPRIN elevations. Direct comparisons between MIS-C and KD revealed only modest, non-significant differences after correction, while SARS-CoV-2 serology status did not affect the main biomarker signals. These findings identify dysregulated MMP/TIMP balance as a central feature of pediatric hyperinflammatory conditions and highlight TIMP-1 as a marker of disease severity.