International journal of molecular sciencesJul 28, 2026

How Cell Cleanup and Inflammation Control May Shift Ongoing Inflammation to Blood Vessel Changes in Kawasaki Disease Resistant to IVIG Treatment

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 3, 2026

Abstract

Intravenous immunoglobulin (IVIG) resistance occurs in 10-20% of children with Kawasaki disease and is associated with a 3- to 5-fold higher risk of coronary artery lesions.

Autophagy dysfunction, especially impaired mitophagy, contributes to sustained inflammation through activation of cGAS-STING.
Neutrophil extracellular traps (NETs) may play a controversial role in Kawasaki disease vasculitis, with PAD2 and PAD4 potentially acting redundantly via the NLRP3 inflammasome.
Endothelial-to-mesenchymal transition (EndMT), driven by the IL-1β/TNF axis and the USP7-TGFβ2/SMAD pathway, is identified as a key event in vascular remodeling.
The proposed 'autophagy-inflammasome axis' may determine whether inflammation resolves or persists in Kawasaki disease.
Candidate biomarkers such as S100A12, mtDNA, and MCM8, along with therapeutic targets like autophagy inducers and NLRP3 inhibitors, could facilitate earlier intervention.

Simplified

Intravenous immunoglobulin (IVIG) resistance occurs in 10-20% of children with Kawasaki disease (KD) and is associated with a 3- to 5-fold higher risk of coronary artery lesions (CALs). Yet the mechanistic basis for why some patients progress from reversible inflammation to irreversible vascular damage after IVIG remains poorly understood. Most existing reviews have focused on risk prediction rather than the mechanistic chain linking resistance to CALs. Here, we synthesize current evidence across three interconnected pathways. First, autophagy dysfunction-particularly impaired mitophagy-sustains inflammation through cGAS-STING activation. Second, neutrophil extracellular traps (NETs) play a controversial role in KD vasculitis, with PAD2 and PAD4 possibly acting redundantly via the NLRP3 inflammasome. Third, endothelial-to-mesenchymal transition (EndMT), driven by the IL-1β/TNF axis and the USP7-TGFβ2/SMAD pathway, emerges as a core event in vascular remodeling. Building on these findings, we propose the "autophagy-inflammasome axis" as a candidate molecular switch that dictates whether inflammation resolves or persists. This hypothesis is actionable: it generates three explicit, testable predictions linking autophagic integrity to inflammatory outcomes and therapeutic response. Direct experimental validation in IVIG-resistant KD models and patient samples is now urgently needed. This review provides a systematic framework for understanding how IVIG resistance transitions to irreversible CALs. It also identifies candidate biomarkers (e.g., S100A12, mtDNA, and MCM8) and therapeutic targets (autophagy inducers, NLRP3 inhibitors, USP7 inhibitors, and anakinra) that could enable earlier intervention.

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How Cell Cleanup and Inflammation Control May Shift Ongoing Inflammation to Blood Vessel Changes in Kawasaki Disease Resistant to IVIG Treatment

Abstract

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