Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
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Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved January 14, 2021 (received for review June 26, 2020)
Significance
Resolution of inflammation, infection, and injury are essential for host defense and homeostasis. Cysteinyl-specialized proresolving mediators (cys-SPMs) are potent chemical signals that accelerate resolution of inflammation, control infection, and display proregenerative properties. We sought evidence for cys-SPM–activated primordial pathways that might link resolution of inflammation and regeneration using planaria because of their robust regenerative ability. RNA sequencing was carried out with surgically resected planaria exposed to cys-SPMs, and we identified genes and pathways regulated by cys-SPMs during the regeneration, including TRAF3. In mammalian systems, TRAF3 contributes to cys-SPM–stimulated phagocyte functions and resolution of infection.
Abstract
The recently elucidated proresolving conjugates in tissue regeneration (CTR) maresin-CTR (MCTR), protectin-CTR (PCTR), and resolvin-CTR (RCTR), termed cysteinyl-specialized proresolving mediators (cys-SPMs) each promotes regeneration, controls infection, and accelerates resolution of inflammation. Here, we sought evidence for cys-SPM activation of primordial pathways in planaria (Dugesia japonica) regeneration that might link resolution of inflammation and regeneration. On surgical resection, planaria regeneration was enhanced with MCTR3, PCTR3, or RCTR3 (10 nM), each used for RNA sequencing. The three cys-SPMs shared up-regulation of 175 known transcripts with fold-change > 1.25 and combined false discovery rate (FDR) < 0.002, and 199 canonical pathways (FDR < 0.25), including NF-κB pathways and an ortholog of human TRAF3 (TNFR-associated factor 3). Three separate pathway analyses converged on TRAF3 up-regulation by cys-SPMs. With human macrophages, three cys-SPMs each dose-dependently increased TRAF3 expression in a cAMP-PKA–dependent manner. TRAF3 overexpression in macrophages enhanced Interleukin-10 (IL-10) and phagocytosis of Escherichia coli. IL-10 also increased phagocytosis in a dose-dependent manner. Silencing of mouse TRAF3 in vivo significantly reduced IL-10 and macrophage phagocytosis. TRAF3 silencing in vivo also relieved cys-SPMs’ actions in limiting polymorphonuclear neutrophil in E. coli exudates. These results identify cys-SPM–regulated pathways in planaria regeneration, uncovering a role for TRAF3/IL-10 in regulating mammalian phagocyte functions in resolution. Cys-SPM activation of TRAF3 signaling is a molecular component of both regeneration and resolution of infectious inflammation.
Footnotes
- ↵1To whom correspondence may be addressed. Email: cserhan{at}bwh.harvard.edu.
Author contributions: N.C. and C.N.S. designed research; N.C., X.d.l.R., and S.L. performed research; N.C., X.d.l.R., S.L., and C.N.S. analyzed data; H.P. and J.M.D. carried out bioinformatics; and N.C. and C.N.S. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2013374118/-/DCSupplemental.
Data Availability
The planaria RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE160278).
Published under the PNAS license.
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Cysteinyl-specialized proresolving mediators link resolution of infectious inflammation and tissue regeneration via TRAF3 activation
Article Classifications
- Biological Sciences
- Immunology and Inflammation
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