Epigenetic reprogramming
Epigenetic reprogramming of innate immune cells is among the most important mechanisms associated with trained immunity. Epigenetic reprogramming involves multiple mechanisms, among which histone modification plays a key role in the induction of macrophage memory.
In the case of Candida infections, monocytes/macrophage memory trained by β-glucan has been found to be associated with epigenetic changes involving the enhanced tri-methylation of histone H3 at lysine 4 (H3K4me3) 13. In addition, in vitro stimulation of human monocytes with oxidized low-density lipoprotein (ox-LDL) has been observed to promote H3K4me3 and the upregulated expression of different inflammatory cytokines associated with atherosclerosis, including IL-6, IL-8, IL-18, and TNF-α 28. On the basis of inflammatory status (the expression of pro-inflammatory mediators, such as TNF-α and IL-6), LPS exposure and β- glucan priming have been shown to induce distinct functional programs of macrophage memory, namely, tolerance and training. The contrasting functional changes in macrophages are associated with specific epigenetic changes such as H3K4me1 and H3K27ac. However, whereas H3K27ac, which marks active promoters and enhancers, is a dynamic modification that gradually disappears after the stimulation subsided, the distal regulatory element (enhancer) marker H3K4me1 remains accessible 11. In conclusion, H3K4me1 may serve as a marker that contributes to maintaining the immunological memory of macrophages.
Additionally, when macrophages are stimulated with low-dose LPS, latent enhancers that are normally inactive, label-free, and unbound by transcription factors are selectively activated and acquired H3K4me1 marks after the resolution of stimulation, and once having been unveiled, the histone marks persist and mediate a stronger pro-inflammatory response upon subsequent stimulation29. Whereas monocytes/macrophages can be stimulated in response to high-dose LPS, the induction of macrophage memory involves H3K9me2 and H3K27me2 modification 30. Kleinnijenhuis et al. 31 have also reported that TLR4-NOD2 is involved in the protective effect of monocytes against secondary reinfection after primary BCG vaccination in healthy volunteers. The enhanced function of monocytes in this case was found to be mediated by H3K4me3, with the production of the inflammatory cytokines IFN-γ, TNF, and IL-1β increasing several-fold in response to infections by non-specific bacterial and fungal pathogens. Moreover, the inhibition of histone methyltransferase was found to be associated with a significant reduction in BCG-induced macrophage memory.
Further factors that play important roles in the induction of macrophage memory are microRNAs (miRNAs), which serve as key regulators of immune cell development and function 32. In this regard, Seeley et al. 33 have reported that prolonged exposure to LPS in mice led to an increase in the expression of miRNA-221 and miRNA-222, followed by transcriptional silencing of certain inflammatory genes through switch/sucrose non-fermentable (SWI/SNF) and signal transducer and activator of transcription (STAT)-mediated chromatin remodeling. This in turn was found to promote immune tolerance to secondary challenge, thereby indicating the regulatory effects of miRNAs in the functional reprogramming of macrophage memory. An enhancement in the expression of miRNA-221 and miRNA-222 has also been established to be associated with immunoparalysis and heightened organ damage in patients with sepsis. In addition to miRNAs, it is conceivable that long non-coding RNAs (lncRNAs) also play roles in macrophage memory. Indeed, Fanucchi et al. 34 found that the newly identified immune gene initiation lncRNA (IPL) directed WD repeat-containing protein 5 (WDR5)-mixed lineage leukemia protein 1 (MLL1) histone methyltransferase complex formation and subsequent H3K4me3 accumulation on the promoters of IL-6, IL-8, and CXCL1, thereby resulting in a stronger inflammatory response in β-glucan-induced trained immunity.