Histones: The critical players in innate immunity

Abstract

The highly conserved histones in different species seem to represent a very ancient and universal innate host defense system against microorganisms in the biological world. Histones are the essential part of nuclear matter and act as a control switch for DNA transcription. However, histones are also found in the cytoplasm, cell membranes, and extracellular fluid, where they function as host defenses and promote inflammatory responses. In some cases, extracellular histones can act as damage-associated molecular patterns (DAMPs) and bind to pattern recognition receptors (PRRs), thereby triggering innate immune responses and causing initial organ damage. Histones and their fragments serve as antimicrobial peptides (AMPs) to directly eliminate bacteria, viruses, fungi, and parasites in vitro and in vivo. Histones are also involved in phagocytes-related innate immune response as components of neutrophil extracellular traps (NETs), neutrophil activators, and plasminogen receptors. In addition, as a considerable part of epigenetic regulation, histone modifications play a vital role in regulating the innate immune response and expression of corresponding defense genes. Here, we review the regulatory role of histones in innate immune response, which provides a new strategy for the development of antibiotics and the use of histones as therapeutic targets for inflammatory diseases, sepsis, autoimmune diseases, and COVID-19.

Targeting circulating high mobility group box-1 and histones by extracorporeal blood purification as an immunomodulation strategy against critical illnesses

“…The results showed that patient survival was significantly worse in groups with higher clearance rates of heat shock protein 70 and HMGB1. Moreover, growing evidence also shows that histones may exert an antimicrobial activity by binding to bacterial nucleic acids and lipopolysaccharides, changing the permeability of the bacterial cell membrane, and inhibiting viral binding and thus playing a vital role in host innate immunity [ 113 ]. Therefore, further clinical studies are urgently needed to determine the thresholds of plasma HMGB1 and histone levels for initiating, monitoring or discontinuing EBP with a balanced immunomodulation effect on the innate and adaptive responses.…”

Synthetic neutrophil extracellular traps dissect bactericidal contribution of NETs under regulation of α-1-antitrypsin

“…Later studies suggest that AAT may also inhibit the NE-mediated degradation of antimicrobial proteins, such as airway-secreted SPLUNC1 ( 49 ), immunoglobulins, and defensins ( 50 ). Histone, which is largely studied in an epigenetic context, is often overlooked in regards to their antimicrobial functions and even more so in their impact in AATD infections ( 51 ). NE has been shown to decrease the cytotoxicity of histone in NET clumps, but its impact on the antimicrobial potency of NETs has not been systematically investigated.…”

Innate Immune Recognition, Integrated Stress Response, Infection, and Tumorigenesis

“…Generally, the S100s proteins are recognized by TLRs or RAGE, the receptor for advanced glycation end-products [ 18 ]. HMGB1 interacts with RAGE and several TLRs (TLR2, TLR4, and TLR9) depending on the cell types [ 19 ], the histones react with TLR2, TLR4, or TLR9, histone H4 is recognized by the TLR4/MD2 heterodimer, and the nucleosome, which is the histone-DNA complex, is the TLR9-specific ligand [ 20 ]. The recognition of tumor-derived DAMPs therefore usually initiates the activation of signaling cascades, thus leading to sterile inflammation, which forms a reinforcing loop of tumorigenesis.…”