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.