Abstract
Epigenetic modulators, including histone methylases, demethylases, and deacetylases, have been implicated previously in the regulation of classical and alternative macrophage activation pathways. In this study, we show that the histone acetyl transferase (HAT) Kat6B (MYST4) is strongly suppressed (>80%) in macrophages by lipopolysaccharide (LPS) (M1 activation), while Kat6A, its partner in the MOZ/MORF complex, is reciprocally upregulated. This pattern of expression is not altered by LPS together with the adenosine receptor agonist NECA (M2d activation). This is despite the observation that miR-487b, a putative regulator of Kat6B expression, is mildly stimulated by LPS, but strongly suppressed by LPS/NECA. Other members of the MYST family of HATs (Kat5, Kat7, and Kat8) are unaffected by LPS treatment. Using the pLightswitch 3′UTR reporter plasmid, the miR-487b binding site in the Kat6b 3′UTR was found to play a role in the LPS-mediated suppression of Kat6B expression, but other as-yet unidentified factors are also involved. As Kat6B is a HAT that has the potential to modulate gene expression by its effects on chromatin accessibility, we are continuing our studies into the potential roles of this epigenetic modulator in macrophage activation pathways.
Highlights
Macrophages are tissue resident phagocytic cells that play key roles in immune responses, tissue debridement, angiogenesis, and wound repair following injury
Our results suggest that the miR-487b site in the 3′ untranslated region (3′UTR) of the Kat6b gene may play a role in regulating the expression of the Kat6b gene, but that other, as-yet unidentified pathways regulated by LPS contribute to the LPSmediated suppression of Kat6b gene expression
As expression of the histone acetyl transferase (HAT) Kat6b was strongly suppressed in response to LPS, we investigated the expression of additional members of the MYST family of genes (MYSTs 1–5) to determine the specificity of this LPS-mediated suppression of Kat6b
Summary
Macrophages are tissue resident phagocytic cells that play key roles in immune responses, tissue debridement, angiogenesis, and wound repair following injury. We have defined a pathway of activation that switches macrophages from an M1 phenotype to an M2-like phenotype that we have previously termed “M2d”, which requires stimulation of TLRs 2, 4, 7, or 9, together with stimulation of adenosine A2A and A2B receptors (A2AR and A2BRs) [13,14,15,16,17,18,19,20] This M2d phenotype is characterized by low expression of inflammatory cytokines, elevated expression of anti-inflammatory cytokines including IL-10, upregulated expression of A2ARs and A2BRs, and strongly upregulated expression of VEGF. Our results suggest that the miR-487b site in the 3′UTR of the Kat6b gene may play a role in regulating the expression of the Kat6b gene, but that other, as-yet unidentified pathways regulated by LPS contribute to the LPSmediated suppression of Kat6b gene expression
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.