The dual role of CCL20 in inflammatory disease: Maintenance of host defense and immunopathological balance.

The chemokine, CCL20, is the only ligand of CCR6 and acts as a molecular switch in immune homeostasis, affecting both protective immunity and pathological inflammation through spatiotemporal regulation of CCR6⁺ leukocytes. CCL20 recruits Th17 cells, γδ T cells and ILC3s, forming synergistic antimicrobial networks with β-defensins and IgA to promote mucosal defense. Chronic CCL20 overexpression caused by NF-κB/MAPK signaling and epigenetic modification is responsible for self-perpetuating inflammation in rheumatoid arthritis, inflammatory bowel disease and psoriasis due to Th17-dominant feedback loops. CCL20 appears to have a role in organizing tertiary lymphoid structures and mediating gut-skin communication, which is affected by gut dysbiosis. Plasmonic nanoarrays and exosome profiling have enabled the discrimination of bioactive CCL20 isoforms with femtogram sensitivity, exposing the possibility for precision biomarker panels. Intelligent delivery systems, such as phase-responsive hydrogels and engineered probiotics, may enable tissue-specific therapeutic modulation. Challenges remain in the balancing of pathway inhibition with mucosal protection and trials of CCR6 antagonists have revealed risks of opportunistic infection. Future directions include dual-modality agents, AI-integrated multi-omics and circadian-timed interventions to preserve host defense during treatment for immunopathology.