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Adv. Sci., 19 January 2025 | https://doi.org/10.1002/advs.202403409 Matrix-Rigidity Cooperates With Biochemical Cues in M2 Macrophage Activation Through Increased Nuclear Deformation and Chromatin Accessibility

Seung Jae Shin ^1,2,^†, Buuvee Bayarkhangai ^1,3,^†, Khaliunsarnai Tsogtbaatar ^1,3, Meng Yuxuan ^1,3, Sang-Hyun Kim ^1,4, Yong-Jae Kim ^1,3, Ali Taghizadeh ^1,3, Daesan Kim ⁵, Dong-Hwee Kim ^5,6,7,^*, Jung-Hwan Lee ^{1,2,3,8,9,10,}^*, Jeongeun Hyun ^1,2,3,8,11,^*, Hae-Won Kim ^{1,2,3,8,10,11,}^*

¹Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116 Republic of Korea
²Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116 Republic of Korea
³Department of Nanobiomedical Sciences & BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116 Republic of Korea

⁴Department of Chemistry, College of Science & Technology, Dankook University, Cheonan, 31116 Republic of Korea
⁵KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841 Republic of Korea

⁶Department of Integrative Energy Engineering, College of Engineering, Korea University, Seoul, 02841 Republic of Korea
⁷Biomedical Research Center, Korea Institute of Science and Technology, Seoul, 02792 Republic of Korea
⁸UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116 Republic of Korea
⁹Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan, 31116 Republic of Korea
¹⁰Cell & Matter Institute, Dankook University, Cheonan, 31116 Republic of Korea
¹¹Department of Regenerative Dental Medicine, School of Dentistry, Dankook University, Cheonan, 31116 Republic of Korea

^†S.J.S. and B.B. contributed equally to this work.
^*Corresponding authors: correspondence to Dong-Hwee Kim, Jung-Hwan Lee, Jeongeun Hyun or Hae-Won Kim

Abstract

Macrophages encounter a myriad of biochemical and mechanical stimuli across various tissues and pathological contexts. Notably, matrix rigidity has emerged as a pivotal regulator of macrophage activation through mechanotransduction. However, the precise mechanisms underlying the interplay between mechanical and biochemical cues within the nuclear milieu remain elusive. Here We elucidate how the increased matrix rigidity drives macrophages to amplify alternatively-activated (M2 phenotype) signaling cooperatively with biochemical cues (e.g., IL4/13) through altered nuclear mechanics. We demonstrate that reconstructed podosome-like F-actins and contractility induce nucleus deformation, opening nuclear pores, which facilitates nuclear translocation of the key transcription factor STAT6. Furthermore, the altered nuclear mechanics increases chromatin accessibility induced by H3K9 methylation, particularly of M2-associated gene promoters. These cooperative events of the mechano-chemical signaling at the cytoskeletal-to-nuclear domains facilitate M2 transcriptional activation and cellular functions. We further evidence the rigidity-primed M2 macrophages are immunosuppressive and accumulated within stiffened tumors in patients. This study proposes a mechanism by which matrix mechanics crosstalks with biochemical signals to potentiate macrophage activation through nuclear mechanosensing and chromatin modifications, offering insights into macrophage mechanobiology and its therapeutic modulations.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-01-21)
연구진국내(교신)+국외 연구진
분야 생명과학 > 구조생물 및 생물물리학

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