Epigenetic Control of Macrophage Shape Transition towards an Atypical Elongated Phenotype by Histone Deacetylase Activity

Abstract

Inflammatory chronic pathologies are complex processes characterized by an imbalance between the resolution of the inflammatory phase and the establishment of tissue repair. The main players in these inflammatory pathologies are bone marrow derived monocytes (BMDMs). However, how monocyte differentiation is modulated to give rise to specific macrophage subpopulations (M1 or M2) that may either maintain the chronic inflammatory process or lead to wound healing is still unclear. Considering that inhibitors of Histone Deacetylase (HDAC) have an anti-inflammatory activity, we asked whether this enzyme would play a role on monocyte differentiation into M1 or M2 phenotype and in the cell shape transition that follows. We then induced murine bone marrow progenitors into monocyte/macrophage differentiation pathway using media containing GM-CSF and the HDAC blocker, Trichostatin A (TSA). We found that the pharmacological inhibition of HDAC activity led to a shape transition from the typical macrophage pancake-like shape into an elongated morphology, which was correlated to a mixed M1/M2 profile of cytokine and chemokine secretion. Our results present, for the first time, that HDAC activity acts as a regulator of macrophage differentiation in the absence of lymphocyte stimuli. We propose that HDAC activity down regulates macrophage plasticity favoring the pro-inflammatory phenotype.

Role of HDACs in normal and malignant hematopoiesis

“…Class I and II HDACs are crucial for the proliferation and differentiation of bone marrow-derived monocytes (BMDMs) into macrophages and DC cells. For instance, under the treatment of TSA (a class I and II HDAC inhibitor), the amplification of murine myeloid progenitors is blocked and, in turn, differentiate into an elongated morphology of mixed M1/M2 profile, instead of the normal pancake-like shape of M1 inflammatory macrophages [37]. In addition, TFs associated with HDAC complexes shows dynamic changes during premonocyte to monocyte differentiation.…”

Macrophage polarization in response to epigenetic modifiers during infection and inflammation

“…Additionally, it also suppresses the expression of cytokines and chemokines of ROS. In addition, macrophages exhibit an overexpression of IL6 and the IL6 receptor (IL6R) when stimulated by LPS [95]. However, the presence of the HDACi ITF2357 has been shown to reduce the expression of IL6 and IL6R [96].…”

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

“…Pharmacological and genetic studies showed that both class I and II HDAC promote an M1 phenotype (recently reviewed in Kapellos and Iqbal, 2016). Consequently, HDAC blockade with the pan-HDAC inhibitor TSA has been reported to polarize macrophages toward an alternatively activated phenotype and to the development of mixed M1/M2 phenotypes (Cabanel et al, 2015). However, epigenetic control of M1 and M2 phenotypes is a complex phenomenon linked to the inherent transient nature of cell polarization, as different activation states can coexist or evolve during disease progression (Martinez and Gordon, 2014), or possibly to the different macrophage populations in the different organs.…”