HSPB1 inhibitor J2 attenuates lung inflammation through direct modulation of Ym1 production and paracrine signaling

Areum Oh, Seulgi Jeon, Mi Gyeong Jeong, Hyo Kyeong Kim, Jio Kang, Yun Sil Lee, Eun Sook Hwang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Heat shock protein beta-1 (HSPB1) is a multifaceted protein that controls cellular stress, modulates cell differentiation and development, and inhibits apoptosis of cancer cells. Increased HSPB1 expression is highly associated with poor outcomes in lung cancer by enhancing cell migration and invasion; therefore, targeting HSPB1 may be a promising therapeutic for lung cancer and fibrosis. Although the HSPB1 inhibitor J2 has been reported to exhibit potent antifibrotic effects, it remains unclear whether and how J2 directly modulates inflammatory immune responses in pulmonary fibrosis. In this study, we found that J2 potently attenuated irradiation or bleomycin-induced pulmonary fibrosis by significantly inhibiting the infiltration and activation of T cells and macrophages. J2 inhibited T-cell proliferation and subsequently suppressed T helper cell development. Although there was no significant effect of J2 on cell proliferation of M1 and M2 macrophages, J2 specifically increased the expression of Ym1 in M2 macrophages without affecting the expression of other M2 markers. Interestingly, J2 increased lysosomal degradation of HSPB1 and inhibited HSPB1-induced repression of signal transducer and activator of transcription 6 (STAT6), which simultaneously increased STAT6 and Ym1 expression. Ym1 production and secretion by J2-treated M2 macrophages substantially decreased IL-8 production by airway epithelial cells in vitro and in vivo, resulting in attenuation of airway inflammation. Taken together, we suggest that J2 has potential as a therapeutic agent for pulmonary fibrosis with increased HSPB1 expression through direct immune suppression by Ym1 production by M2 macrophages as well as T-cell suppression.

Original languageEnglish
Article number112225
JournalBiomedicine and Pharmacotherapy
Volume143
DOIs
StatePublished - Nov 2021

Keywords

  • Antifibrosis
  • HSPB1
  • J2
  • M2 macrophages
  • STAT6
  • Ym1

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