Memory Macrophages

Abstract

Immunological memory is a crucial part of the immune defense that allows organisms to respond against previously encountered pathogens or other harmful factors. Immunological memory is based on the establishment of epigenetic modifications of the genome. The ability to memorize encounters with pathogens and other harmful factors and mount enhanced defense upon subsequent encounters is an evolutionarily ancient mechanism operating in all animals and plants. However, the term immunological memory is usually restricted to the organisms (invertebrates and vertebrates) possessing the immune system. The mammalian immune system, with innate and adaptive branches, is the most sophisticated among vertebrates. The concept of innate memory and memory macrophages is relatively new and thus understudied. We introduce the concept of immunological memory and describe types of memory in different species and their evolutionary status. We discuss why the traditional view of innate immune cells as the first-line defenders is too restrictive and how the innate immune cells can accumulate and retain immunologic memory. We describe how the initial priming leads to chromatin remodeling and epigenetic changes, which allow memory macrophage formation. We also summarize what is currently known about the mechanisms underlying development of memory macrophages; their molecular and metabolic signature and surface markers; and how they may contribute to immune defense, diseases, and organ transplantation.

Keywords: epigenetic modifications; innate immunological memory; macrophage; trained immunity; transplantation.

Figure 1

Development of memory macrophage.(A) Naïve (unstimulated) macrophage expresses pattern recognition receptors PRSs, such as Toll-like receptors (TLRs) and non-TLR antigen-recognition receptors, such as C-type lectin receptors (CLRs), which recognize pathogen-associated molecular patterns (PAMPs). For example, TLR-4 recognizes lipopolysaccharide (LPS) of Gram-negative bacteria, and CLR receptor Dectin-1 recognizes β-glucans present in bacteria and fungi. In the naive macrophage, the pro-inflammatory genes are transcriptionally silent via, for example, the trimethylated H3K27 (H3K27me3). (B) The binding of PAMs molecule to its receptor induces histone modifications at the gene promoter, such as trimethylation of H3K4 (H3K4me3) and acetylation of H3K27 (H3K27ac). In addition, the enhancer region becomes enriched with monomethylated H3K4 (H3K4me1) and H3K27ac. Activated pro-inflammatory genes transcribe mRNAs, which after transport to the cytoplasm, are translated into the pro-inflammatory cytokines, such as IL-6 and TNF-α, which fight the pathogen. (C) After pathogen elimination, some histone modifications in the macrophage are lost, but some remain as the epigenetic marks. The immunological memory of the first encounter with the pathogen becomes imprinted in the macrophage genome. (D) The state of transcriptional alertness of memory macrophage allows for faster and stronger pro-inflammatory response upon a second encounter with the same or different pathogens.

Figure 2

Chromatin structure and epigenetic marks during the development of memory macrophages. (A) In naïve (unstimulated) macrophages, the regions of chromatin housing the immune response genes are highly condensed (heterochromatin state) due to high methylation of DNA, making these genes inaccessible to the transcription factors. This results in complete silencing or very low transcription and translation of the immune response genes. (B) Primary stimulation with the pathogen or danger signals demethylates DNA, decondenses chromatin (euchromatin state), and methylates and acetylates histones (for example, H3K4me3, H3K27ac) reading the immune gene for transcription. A high level of transcription followed by translation produces a high level of immune response factors. (C) After cessation of the stimulus, chromatin only partially condenses, and the remaining epigenetic marks (for example, H3K4me1) keep resting memory macrophage in the state of transcriptional alertness. (D) The secondary challenge, with the same or different pathogen, induces chromatin decondensation, demethylation of DNA, and modification of histones (such as H3K4me3, H3K4me1, and H3K27ac) allowing robust transcription and subsequent high production of immune response factors. Modified from [54].