Key result
Necrotic cardiac myocyte proteins trigger classical macrophage activation, increasing phagocytosis and IL-1β.
Why the study?
Although macrophages are essential for myocardial repair and regeneration, the effect of damage-associated molecular patterns released by necrotic and dying cells on macrophage activation remained unclear.
Proteins released from necrotic cardiac myocytes are sufficient to skew macrophage polarization towards a classically activated, pro-inflammatory phenotype.
Answers are grounded in this paper and cite their sources.
Necrotic myocyte proteins may drive post-MI macrophage activation; hypothesis-generating for targeted anti-inflammatory therapies.
Necrotic and dying cells release damage-associated molecular patterns (DAMPs) that can initiate sterile inflammatory responses in the heart. Although macrophages are essential for myocardial repair and regeneration, the effect of DAMPs on macrophage activation remains unclear. To address this gap in knowledge we studied the effect of necrotic cardiac myocyte extracts on primary peritoneal macrophage (PPM) cultures in vitro. We first performed unbiased transcriptomic profiling with RNA-sequencing of PPMs cultured for up to 72 hours in the presence and absence of: 1) necrotic cell extracts (NCEs) from necrotic cardiac myocytes in order to mimic the release of DAMPs; 2) lipopolysaccharide (LPS), which is known to polarize macrophages towards a classically activated phenotype and 3) Interleukin-4 (IL-4), which is known to promote polarization of macrophages towards an alternatively activated phenotype. NCEs provoke changes in differential gene expression (DEGs) that had considerable overlap with LPS-induced changes, suggesting that NCEs promote macrophage polarization towards a classically activated phenotype. Treating NCEs with proteinase-K abolished the effects of NCEs on macrophage activation, whereas NCE treatment with DNase and RNase did not affect macrophage activation. Stimulation of macrophage cultures with NCEs and LPS resulted in a significant increase in macrophage phagocytosis and interleukin-1β secretion, whereas treatment with IL-4 had no significant effect on phagocytosis and interleukin-1β. Taken together, our findings suggest that proteins released from necrotic cardiac myocytes are sufficient to skew the polarization of macrophages towards a classically activated phenotype.
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Jiang et al. (2023) studied Myocardial inflammation. Necrotic cell extracts (NCEs) from necrotic cardiac myocytes vs. Absence of NCEs, lipopolysaccharide (LPS), and Interleukin-4 (IL-4) was evaluated on Macrophage polarization (differential gene expression, phagocytosis, and interleukin-1β secretion). Proteins released from necrotic cardiac myocytes are sufficient to skew the polarization of primary peritoneal macrophages towards a classically activated phenotype, increasing phagocytosis and IL-1β.
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