RELMα licenses macrophages for damage-associated molecular pattern activation to instigate pulmonary vascular remodeling

Qing Lin, Chunling Fan, John T. Skinner, Elizabeth N. Hunter, Andrew A. MacDonald, Peter B. Illei, Kazuyo Yamaji-Kegan, Roger A. Johns

Research output: Contribution to journalArticlepeer-review

Abstract

Pulmonary hypertension (PH) is a debilitating disease characterized by remodeling of the lung vasculature. In rodents, resistin-like molecule-a (RELMα, also known as HIMF or FIZZ1) can induce PH, but the signaling mechanisms are still unclear. In this study, we used human lung samples and a hypoxia-induced mouse model of PH. We found that the human homolog of RELMα, human (h) resistin, is upregulated in macrophage-like inflammatory cells from lung tissues of patients with idiopathic PH. Additionally, at PH onset in the mouse model, we observed RELMα-dependent lung accumulation of macrophages that expressed high levels of the key damage-associated molecular pattern (DAMP) molecule high-mobility group box 1 (HMGB1) and its receptor for advanced glycation end products (RAGE). In vitro, RELMα/hresistin-induced macrophage-specific HMGB1/RAGE expression and facilitated HMGB1 nucleus-to-cytoplasm translocation and extracellular secretion. Mechanistically, hresistin promoted HMGB1 posttranslational lysine acetylation by preserving the NAD+-dependent deacetylase sirtuin (Sirt) 1 in human macrophages. Notably, the hresistin-stimulated macrophages promoted apoptosis-resistant proliferation of human pulmonary artery smooth muscle cells in an HMGB1/RAGE-dependent manner. In the mouse model, RELMα also suppressed the Sirt1 signal in pulmonary macrophages in the early posthypoxic period. Notably, recruited macrophages in the lungs of these mice carried the RELMα binding partner Bruton tyrosine kinase (BTK). hResistin also mediated the migration of human macrophages by activating BTK in vitro. Collectively, these data reveal a vascular-immune cellular interaction in the early PH stage and suggest that targeting RELMα/DAMP-driven macrophages may offer a promising strategy to treat PH and other related vascular inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)2862-2871
Number of pages10
JournalJournal of Immunology
Volume203
Issue number11
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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