The first wave of cells

The first wave of BMS345541 hydrochloride infiltrating heart shortly after MI is composed mainly of neutrophils, with the highest number on the first day after ischemic episode [101]. These cells are recruited via C-X-C motif chemokine ligand-2 (CXCL-2)- and CXCL-5-mediated chemotaxis. Both chemokines are produced by cardiac macrophages [102]. Neutrophils are followed by monocytes. In mice, there are two main subsets of monocytes that differ in expression of Ly6C and CD43. Classical monocytes are described as Ly6Chigh CD43low and regarded as inflammatory. They are able to enter the damaged or inflamed tissue and differentiate into macrophages. This process of migration is mainly driven by CCR2-monocyte chemoattractant protein-1 (MCP-1, CCL2) axis, as CCR2 is strongly expressed by classical monocytes [3]. Additionally, classical monocytes may transdifferentiate into nonclassical Ly6Clow CD43high monocytes which do not express CCR2. Nonclassical monocytes patrol the intravascular endothelial cell surface and clear dying endothelial cells [3,103]. Sometimes a third intermediate population is distinguished and characterized by high expression of both Ly6C and CD43 [104]. In humans, there are at least 3 subsets of monocytes: CD14high CD16- similar to murine classical monocytes, proinflammatory CD14high CD16+, and CD14+CD16high similar to murine nonclassical monocytes [105]. Monocytes may be recruited to ischemic tissue even 30 minutes following MI [101] and within few days they differentiate into macrophages, exhibiting reparative phenotype [106]. In the later chronic phase of inflammation, macrophages are maintained, again, by local proliferation rather than further monocyte recruitment [107]. Importantly, monocytes invading ischemic myocardium are not solely generated in bone marrow, but also in extramedullary sites, such as spleen [108]. It was reported, that around 40% of Ly6Chigh monocytes found in the myocardium after MI are of splenic origin [109]. Moreover, studies have shown that generation of monocytes in spleen in response to MI may contribute to the acceleration of atherosclerosis [110]. Interestingly, HO-1 expression is linked to the number of Ly6Chigh monocytes. Hinkel et al. demonstrated that the influx of immune cells, including Ly6Chigh monocytes, to the ischemic heart is exacerbated in the absence of HO-1 [111]. On the other hand, cardiac overexpression of HO-1 with gene therapy was able to revert this process [111]. Our recent findings confirmed these observations. A more potent deterioration of post-MI LV function observed in HO-1 knockout mice was accompanied by higher numbers of Ly6Chigh monocytes in peripheral blood and greater numbers of proinflammatory macrophages in the heart [103] (Fig. 4), what can be related to the higher expression of adhesion molecules (vascular cell adhesion molecule 1 – VCAM1, intercellular adhesion molecule 1 – ICAM1, E-selectin) in the absence of HO-1. Additionally, we identified spleen as an important source of these cells [103] (Fig. 4). It was recently demonstrated that HO-1 affects granulopoiesis in mice through regulation of myelocyte proliferation accompanied by changes in expression of transcriptionally active C/EBPβ protein [112]. But, the mechanism by which HO-1 regulates the production of monocytes remains to be elucidated. During past few years, the old model suggesting that tissue macrophages originate from circulating blood monocytes was extensively revised. There is plenty of evidence suggesting that tissue macrophages are of embryonic origin and thanks to in situ proliferation they persist into adulthood in the tissue independently of monocytes [[113], [114], [115], [116]]. Interestingly, fate mapping driven by CD115 revealed that yolk-sac derived macrophages persist into adulthood in substantial numbers only in the heart, liver and brain [117]. The same study demonstrated that cardiac tissue macrophages are established during embryonic development, independently of definitive hematopoiesis in the fetal liver. In the adult murine heart there are plenty of macrophage populations. The first one is embryonically established and separates from blood monocytes. These cells do not express CCR2. Among them, there are MHC-IIlow Ly6C-, MHC-IIhigh Ly6C- and Ly6C+ subsets (Fig. 5, Table 2). The other population is low in number, derived from blood monocytes and characterized as CCR2+ Ly6Chigh [117] (Fig. 5, Table 2). Interestingly, neonatal heart contains mainly embryonically established, MHC-IIlow CCR2- macrophages [118] (Fig. 5, Table 2). Several studies demonstrated that rodent neonatal heart is able to regenerate after serious damage including apical resection [119], MI [120] or cryoinfarction [121]. What is more, this phenomenon depends on the local expansion of cardiac CCR2- macrophages of embryonic origin, which are necessary for the regeneration [118,122]. Embryonic-derived macrophages in the injured neonatal heart are able to promote proliferation of cardiomyocytes and stimulate coronary angiogenesis, and simultaneously produce minimal inflammation [118]. Taking into account the proangiogenic and anti-inflammatory properties of HO-1, it would be interesting to investigate the role of HO-1 in neonatal macrophage biology under cardiac damage conditions.