Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct

Abstract

Key Points Alternatively activated macrophages derived from monocytes and tissue macrophages have distinct transcriptional profiles and phenotypes. Monocyte-derived AAMs are more involved with immune regulation than tissue-derived AAMs.

Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression

“…(16), our findings are in agreement with recent reports that Ly6C hi inflammatory monocytes recruited to allergic skin, schistosome granulomas, or injured myocardium subsequently acquired the M2 phenotype (20,(28)(29)(30)(31). Acute inhibition of CCR2 prevents plaque regression and suppresses enrichment in the M2 macrophage phenotype.…”

MicroRNA-33–dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis

“…M2 macrophages are also a source of inhibitory cytokines such as IL-10 and TGF-β, which help to resolve inflammation and have been shown to protect from atherosclerosis (57,58). Moreover, of particular relevance to the present report, myeloid cells treated in vitro with M2-polarizing factors (e.g., IL-4, PPARγ agonists) and in vivo monocyte-derived M2 macrophages have recently been shown to express high levels of retinal dehydrogenase (ALDH1A2/RALDH), the rate-limiting enzyme for the production of retinoic acid, which, together with TGF-β, can promote the differentiation and expansion of a population of FoxP3 + Tregs known as iTregs (5)(6)(7)59). iTregs develop extrathymically in response to several soluble mediators, including TGF-β, IL-2, and retinoic acid, and in the gut, retinoic acid-mediated trafficking of T cells has been shown to be required for expansion of iTreg numbers (60).…”

“…Furthermore, miR-33 overexpression failed to increase markers of M1 macrophage activation (Il6, Nos2, Il1b) in Ampk -/-macrophages consistent with a loss of metabolic reprogramming by miR-33 in the absence of AMPK ( Figure 2G). Similarly, miR-33 inhibition failed to reduce ECAR or increase OCR in Ampk -/-macrophages, and this was paralleled by a loss of macrophage polarization to the M2 phenotype ( Figure 2, H Figure 4A), a gene recently reported to be expressed in alternatively activated macrophages (6). Aldh1a2 codes for the enzyme retin ALDH type 2 (RALDH2), which regulates the synthesis of retinoic acid, a metabolite with immunoregulatory function (7).…”

“…collagen), and catecholamines (4). Moreover, monocyte-derived M2 macrophages were recently shown to be an important source of retinoic acid (5), a hormonelike metabolite that promotes the differentiation of immunosuppressive Tregs (6,7).…”

“…For intracellular nuclear staining of FOXP3, cells were washed with PhosFlow permeabilization buffer (BD Biosciences) and blocked with anti-mouse CD16/32 following surface staining with antibodies against CD4 and CD25, and stained with a FOXP3 antibody (PE-CF594, BD Biosciences) for 1 hour at 4°C in Foxp3/Transcription Factor Fixation/Permeabilization Concentrate and Diluent (eBioscience) as previously described (5). ALDH activity was measured using the ALDEFLUOR staining kit (StemCell Technologies) in the presence of the ALDH inhibitor DEAB (15 μM), as previously described (5,6). In this assay, BODIPY aminoacetaldehyde, the nontoxic substrate for ALDH that is able to diffuse freely into cells, is converted by ALDH into BODIPY aminoacetate, a fluorescent product that is retained in cells and can be detected using flow cytometry.…”