Abstract
Citrullinated histone epitopes are involved in the very early stages of inflammatory responses. An important early event is the activation of neutrophils. It has been shown that Peptidyl Arginine Deiminase (PAD) expression levels increase upon pro-inflammatory signalling followed by activation of neutrophils. Subsequently, PAD enzymes cause histone citrullination in the activated neutrophils. Histone citrullination is involved in various processes. One of the most important is NETosis, which results in the release of citrullinated histones to the extracellular space. There, they are involved in Neutrophil Extracellular Trap (NET) formation, which intensifies the inflammatory response. The central role of citrullinated histones in early inflammation makes NETs an attractive target for inflammatory disease intervention. Moreover, the safety profile is expected to be superior to immune-suppressing biologicals, like anti- Tumour Necrosis Factor (TNF) drugs. It is anticipated that shielding citrullinated histone epitopes from the immune system, as well as interfering with their putative roles in the inflammatory response, will have a broad applicability in preventing and treating various inflammatory diseases, including multiple sclerosis.
Highlights
Protein citrullination, a post-translational modification (PTM) of peptidylarginine, plays an important role in the normal functioning of the immune system, and in physiological processes such as skin keratinization, the insulation of neuronal axons, the plasticity of the central nervous system (CNS), and in gene regulation [1]
Citrullination has become an area of significant interest, because of its suspected role in various pathological conditions, such as rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, chronic obstructive pulmonary disease (COPD), and neurodegenerative diseases like Alzheimer’s disease (AD) [2]
Citrullination is a PTM that is catalysed by peptidylarginine deiminases (PADs)
Summary
A post-translational modification (PTM) of peptidylarginine, plays an important role in the normal functioning of the immune system, and in physiological processes such as skin keratinization, the insulation of neuronal axons, the plasticity of the central nervous system (CNS), and in gene regulation [1]. Citrullination plays an important role in human and animal cancers through its role in gene regulation [1,3,4]. It is unclear whether citrullination is the cause or the consequence of these pathological disorders [1]. In recent overviews by Baka et al [1] and Mohanan et al [4], important aspects of citrullination under both physiological and pathological conditions are discussed. We discuss various aspects of citrullination and the possibility to target the citrullination process as a therapeutic approach to treat inflammatory (autoimmune) diseases
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