Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

Abstract

Despite several therapies are currently available to treat inflammatory diseases, new drugs to treat chronic conditions with less side effects and lower production costs are still needed. An innovative approach to drug discovery, the Connectivity Map (CMap), shows how integrating genome-wide gene expression data of drugs and diseases can accelerate this process. Comparison of genome-wide gene expression data generated with Annexin A1 (AnxA1) with the CMap revealed significant alignment with gene profiles elicited by histone deacetylase inhibitors (HDACIs), what made us to hypothesize that AnxA1 might mediate the anti-inflammatory actions of HDACIs. Addition of HDACIs (valproic acid, sodium butyrate and thricostatin A) to mouse macrophages caused externalization of AnxA1 with concomitant inhibition of cytokine gene expression and release, events that occurred independently since this inhibition was retained in AnxA1 null macrophages. However, novel AnxA1-mediated functions for HDACIs could be unveiled, including promotion of neutrophil apoptosis and macrophage phagocytosis, both steps crucial for effective resolution of inflammation. In a model of acute resolving inflammation, administration of valproic acid and sodium butyrate to mice at the peak of disease accelerated resolution processes in wild type, but much more modestly in AnxA1 null mice. Deeper analyses revealed a role for endogenous AnxA1 in the induction of neutrophil death in vivo by HDACIs. In summary, interrogation of the CMap revealed an unexpected association between HDACIs and AnxA1 that translated in mechanistic findings with particular impact on the processes that regulate the resolution of inflammation. We propose non-genomic modulation of AnxA1 in immune cells as a novel mechanism of action for HDACIs, which may underlie their reported efficacy in models of chronic inflammatory pathologies.

Histone deacetylase inhibitors decrease intra-abdominal adhesions with one intraoperative dose by reducing peritoneal fibrin deposition pathways

“…49 Further investigation revealed an association between HDACIs and the expression of annexin A1, an anti-inflammatory membrane-bound protein that has been shown to have a particular impact on the processes that regulate the resolution of acute inflammation. 50 These studies further propose nongenomic modulation of annexin A1 in immune cells as a novel mechanism of action for HDACIs, which presumably underlies their reported efficacy in other inflammatory pathologies including perhaps the formation of adhesions.…”

Butyrate Modulates Inflammation in Chondrocytes via GPR43 Receptor

“…The resolution process is mediated by several factors, including AnxA1 [49]. Recent data demonstrated the positive correlation between HDACs inhibitors and the anti-inflammatory and pro-resolving AnxA1 [50]. Defective inflammation resolution or its dysregulation is involved in several chronic inflammatory disease including arthritis, asthma and cardiovascular disease [51].…”

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

“…AnxA1 also acts on the resolution phase of inflammation by inducing apoptosis of neutrophils (14,15) and increasing efferocytosis by macrophages (16,17). Importantly, AnxA1 production and activities are involved in proresolution effects of GCs (18) and histone deacetylase inhibitors (19). Recently, it was demonstrated in vitro that GILZ is a target of the anti-inflammatory effects of AnxA1 (20).…”