Abstract
Carbon monoxide (CO) is generated by heme oxygenase (HO), and HO-1 is highly induced in monocytes and macrophages upon stimulation. Monocytes differentiate into macrophages, including pro-inflammatory (M1) and anti-inflammatory (M2) cells, in response to environmental signals. The present study investigated whether CO modulates macrophage differentiation and polarization, by applying the CO-releasing molecule-3 (CORM-3). Results showed that murine bone marrow cells are differentiated into macrophages by CORM-3 in the presence of macrophage colony-stimulating factor. CORM-3 increases expressions of macrophage markers, including F4/80 and CD11b, and alters the cell morphology into elongated spindle-shaped cells, which is a typical morphology of M2 cells. CORM-3 upregulates the expressions of genes and molecules involved in M2 polarization and M2 phenotype markers, such as STAT6, PPARγ, Ym1, Fizz1, arginase-1, and IL-10. However, exposure to CORM-3 inhibits the iNOS expression, suggesting that CO enhances macrophage differentiation and polarization toward M2. Increased HO-1 expression is observed in differentiated macrophages, and CORM-3 further increases this expression. Hemin, an HO-1 inducer, results in increased macrophage differentiation, whereas the HO-1 inhibitor zinc protoporphyrin IX inhibits differentiation. In addition, CORM-3 increases the proportion of macrophages in peritoneal exudate cells and enhances the expression of HO-1 and arginase-1 but inhibits iNOS. Taken together, these results suggest that the abundantly produced CO in activated macrophages enhances proliferation, differentiation, and polarization toward M2. It will probably help clear apoptotic cells, resolve inflammation, and promote wound healing and tissue remodeling.
Highlights
Heme oxygenase (HO) produces carbon monoxide (CO) in most cell types during the catabolism of heme, along with biliverdin/bilirubin and free iron [1,2]
Murine bone marrow cells (BMCs) were differentiated into macrophages in the presence of macrophage colony-stimulating factor (M-CSF); around 60% of cells were F4/80-positive on day 8 and more than 80% of cells were F4/80-positive on days 10–12 (Figure 1A)
The exogenous administration of CO mimics the effects of HO-1 activation, and, the BMCs were treated with CO-releasing molecule-3 (CORM-3)
Summary
Heme oxygenase (HO) produces carbon monoxide (CO) in most cell types during the catabolism of heme, along with biliverdin/bilirubin and free iron [1,2]. HO-1 expression is regulated by the redox-sensitive transcription factor, the nuclear factor (erythroid-derived 2)-like 2 (Nrf). HO-1 expression is regulated by the redox-sensitive transcription factor, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) It is highly induced in macrophages when exposed to oxidative stress and inflammation and during differentiation [3,4]. Monocytes differentiate into macrophages after migrating out of the blood vessel and are polarized into various subsets by multiple signals in all tissues [8]. M1 polarization occurs in the presence of interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and lipopolysaccharide (LPS) via signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 5 (IRF5), or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), whereas fungal and helminth infections, interleukin (IL)-4, IL-10, IL-13, and tumor growth factor (TGF)-β skew macrophages toward M2 via STAT6, peroxisome proliferator-activated receptor γ (PPARγ), PPARδ, or Jumonji domain-containing protein D3 [8,13]. The plasticity of macrophages is proven by re-polarization of already differentiated macrophages when M2 are exposed to M1 signals or vice versa [14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
