Blockade of TLR2 activation in macrophages ameliorates psoriasis-like skin inflammation
- 주제(키워드) Psoriasis , macrophage , TLR2 , inflammation , hyaluronic acid nanoparticle
- 주제(DDC) 547
- 발행기관 아주대학교 일반대학원
- 지도교수 Wook Kim
- 발행년도 2026
- 학위수여년월 2026. 2
- 학위명 박사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000035637
- 본문언어 한국어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Self-assembled hyaluronic acid nanoparticles (HANPs) exhibit promising therapeutic effects against psoriasis, yet their precise targets and molecular mechanisms remain inadequately explored. Here, I demonstrate that HANPs target toll-like receptor 2 (TLR2) to alleviate psoriatic skin inflammation in preclinical settings. This action is mediated by the HA-derived hydrophilic shell surrounding the NPs, rather than free HA or the hydrophobic core. Mechanistically, HANPs inhibited TLR2-driven macrophage differentiation into the pro-inflammatory M1 phenotype, suppressing Il1b, Tnf, and Nlrp3 expression by 60–80%. HANPs also blocked downstream NF-κB, MAP kinase, and NLRP3 inflammasome activation, leading to a ~65% reduction in mature IL-1β secretion. Importantly, TLR2 expression was markedly elevated in the psoriatic skin of both mouse models and human patients. Transcutaneous administration of HANPs significantly alleviated imiquimod-induced psoriasis-like dermatitis, reducing epidermal thickness by ~35%, improving skin barrier function, and exhibiting no observable toxicity. Notably, these therapeutic effects were not observed in Tlr2- deficient mice, confirming the specificity of TLR2 targeting by HANPs. My findings uncover the anti-inflammatory mechanism of HANPs and position them as a promising strategy for psoriasis therapy. Keywords: Psoriasis, macrophage, TLR2, hyaluronic acid nanoparticle
more목차
Ⅰ. Introduction 1
1. Psoriasis 1
2. Role of TLR2 in macrophages 1
3. Therapeutic potential of hyaluronic acid nanoparticles 3
4. Aim of the study 4
Ⅱ. Materials and Methods 5
1. Materials 5
2. HACN synthesis 5
2.1. CA Ester 5
2.2. Ethylenediamine-conjugated CA (EtCA) 5
2.3. HA-CA conjugate 5
2.4. Characterization of HACNs 6
3. Determination of EtCA levels within HACNs using a fluorescamine assay 6
4. Colorimetric assessment for hyaluronidase-mediated degradation of HACN 7
5. Surface plasmon resonance analysis 7
6. Cell culture 7
7. In vitro macrophage polarization 8
8. Analysis of HACN binding to polarized macrophages 8
9. Flow cytometric analysis 9
10. Quantitative real-time PCR analysis 9
11. Enzyme-linked immunosorbent assay 11
12. Western blot analysis 11
13. NLRP3 inflammasome activity 12
14. Analysis of gene expression using public databases 12
15. Library preparation and RNA sequencing 12
16. Bioinformatical analysis for RNA-seq 13
17. Animals 13
18. Preclinical psoriasis mouse models 13
19. In vivo safety 14
20. Histology 15
21. Statistical analysis 15
Ⅲ. Results 16
1. Physicochemical characteristics of self-assembled HANPs 16
2. Modulation of macrophage M1 polarization by direct binding to TLR2 21
3. Spherical NP formation is essential for HACN efficacy 24
4. TLR2 signaling pathways modulated by HACNs 30
5. TLR2 as a target in psoriasis-like skin inflammation 33
Ⅳ. Discussion 47
Ⅴ. Conclusion 50
Ⅵ. References 51
Ⅶ. 국문 초록 55
