Byline: Andis. Klegeris
Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis, but they also contribute to various neurological disorders, including neurotrauma, stroke, and demyelinating or neurodegenerative diseases. Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins, which can be broadly divided into the pro-inflammatory damage-associated molecular patterns (DAMPs) and anti-inflammatory resolution-associated molecular patterns (RAMPs), even though there is notable overlap between the DAMP- and RAMP-like activities for some of these molecules. Both groups of molecular patterns were initially described in peripheral immune processes and pathologies; however, it is now evident that at least some, if not all, of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders. The review of recent literature demonstrates that studies on DAMPs and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts. Nevertheless, this review also reveals that over the last five years, significant advances have been made in our understanding of the neuroimmune functions of several well-established DAMPs, including high-mobility group box 1 protein and interleukin 33. Novel neuroimmune functions have been demonstrated for other DAMPs that previously were considered almost exclusively as peripheral immune regulators; they include mitochondrial transcription factor A and cytochrome C. RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions, such as multiple sclerosis and rheumatoid arthritis. The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is also supported by several of the identified studies. It can be concluded that further studies of DAMPs and RAMPs of the central nervous system will continue to be an important and productive field of neuroimmunology.
Damage-associated molecular patterns (DAMPs), also known as danger-associated molecular patterns and alarmins, are endogenous molecules that can be released into the extracellular space upon cellular stress or damage. DAMPs are an integral part of immune response; at low concentrations, these molecules regulate homeostasis and correct altered physiological states, but at high concentrations, they enhance and propagate inflammatory reactions. Excessive release of DAMPs as a result of trauma or inflammatory processes leads to immune activation of surrounding cells and recruitment of distant cells. This causes further tissue injury, thus establishing vicious cycles of damage, which may lead to chronic inflammation (Patel, 2018). The concept of DAMPs as immunoregulators was introduced in the 1990s, and since then the number of molecules included in this group has been steadily increasing. Molecules that are normally located intracellularly are most often considered DAMPs. They originate from the nucleus (e.g., genomic DNA, high-mobility group box 1 protein (HMGB1), interleukin (IL)-33), cytosol (e.g., heat-shock proteins (HSPs), S100 proteins), mitochondria (e.g., ATP, mitochondrial DNA, cytochrome C), endoplasmic reticulum (e.g., calreticulin), or granules (e.g., defensins). Some researchers also consider extracellular...