MAP1S limits autoimmune uveitis by suppressing Th17 differentiation through dual Control of the EGR2-LCN2 axis and...

Autoimmune uveitis is a vision-threatening inflammatory disorder driven by dysregulated T helper 17 (Th17) responses, yet therapeutic strategies targeting Th17 differentiation are lacking. Through transcriptomic screening of an experimental autoimmune uveitis (EAU) model and validation in peripheral blood mononuclear cells from Vogt-Koyanagi-Harada patients, we identified MAP1S (microtubule-associated protein 1S) as a pivotal, conserved regulator. Here, we demonstrate that MAP1S constrains pathogenic Th17 responses and alleviates EAU through a dual mechanism coordinating transcriptional control and autophagic degradation. Mechanistically, MAP1S binds to EGR2 (early growth response 2) and restrains its acetylation at Lys368, thereby suppressing Lcn2 (lipocalin 2) transcription. Besides, MAP1S facilitates autophagosome biogenesis and lysosomal trafficking, promoting the autophagic clearance of LCN2 protein. Notably, MAP1S deficiency enhances EGR2 acetylation, increases Lcn2 transcription, disrupts autophagosome trafficking, impairs LCN2 degradation, and promotes LCN2 accumulation, collectively driving Th17 polarization and exacerbating EAU pathology. Adoptive transfer of cervical lymph node cells from map1s knockout mice reproduced severe disease in wild-type recipients. Moreover, pharmacological activation of MAP1S with spermidine suppressed Th17 responses and alleviated disease severity. Our findings establish MAP1S as a critical node integrating acetylation signaling of EGR2 and autophagic flux to govern LCN2 homeostasis and Th17 pathogenicity, revealing a promising therapeutic target for autoimmune uveitis and potentially other Th17-mediated diseases.Abbreviations: AAV: adeno-associated virus; ACOD1: aconitate decarboxylase 1; AU: autoimmune uveitis; BCL2: B cell leukemia/lymphoma 2; CDLNs: cervical draining lymph nodes; CFA: complete Freund's adjuvant; ChIP: chromatin immunoprecipitation; Co-IP: co-immunoprecipitation; CQ: chloroquine; EAU: experimental autoimmune uveitis; EGR2: early growth response 2; GDF15: growth differentiation factor 15; HDAC4: histone deacetylase 4; HDAC6: histone deacetylase 6; IL17: interleukin 17; IL17f: interleukin 17f; IL22: interleukin 22; K: lysine; KAT2A/GCN5: K(lysine) acetyltransferase 2A; KO: knockout; LCN2: lipocalin 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1S: microtubule-associated protein 1S; MS: mass spectrometry; PBMC: peripheral blood mononuclear cell; PCR: polymerase chain rection; PPI: protein-protein interaction; PTX: pertussis toxin; qPCR: quantitative PCR; RT-qPCR: reverse transcription and quantitative real-time RCR; SAA3: serum amyloid A3; SPD: spermidine; Th1 cells: T helper 1 cells; Th17 cells: T helper 17 cells; TF: transcriptional factor; T_regcells: regulatory T cells; VKH disease: Vogt-Koyanagi-Harada disease; WT: wild-type.