Neuroinflammation is a complex process that involves both the Central Nervous System (CNS) and the peripheral circulation, which is considered to be associated with many neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and depression.
This inflammation usually involves the activation of glial cells, the release of inflammatory mediators such as cytokines and chemokines, and the production of reactive oxygen species and secondary messengers. Pro-inflammatory cytokines like tumor necrosis factor alpha (TNFa) and interleukin -1 beta (IL-1B), the NF-kB and MAPK cell signaling pathways, and the neuroinflammatory regulator TREM-2 are some of the factors involved in orchestrating immune responses within the CNS.
Additionally, microglia and macrophage markers, Toll-like receptors (TLRs), and anti-inflammatory cytokines such as IL-10 and TGF-β are key players in the neuroinflammatory landscape. Biomarkers like GFAP and MBP further aid in diagnosing and monitoring neuroinflammatory diseases. Emerging trends in neuroinflammation research include the use of brain organoids, cultivated from pluripotent stem cells with the assistance of various cytokines and growth factors, offering a physiologically relevant platform to study intricate cellular and molecular interactions in controlled environments.
Figure 1. Schematic depiction of shared molecular signaling cascade among protein aggregates associated with Alzheimer's disease, tauopathies, and Parkinson's disease. This cascade is initiated by the activation of microglia in response to signals of cellular damage.
The occurence of nueroinflammation
Neuroinflammation is an immune response activated by microglia and astrocytes in the CNS, playing crucial roles in the development of neurodegenerative diseases such as Parkinson's, Alzheimer's, schizophrenia, and major depression, including autophagy dysfunction, CNS lymphatic drainage dysfunction, and traumatic brain injury.
It is commonly believed that protein aggregation in the central nervous system can induce neuroinflammation. However, there is growing evidence that inflammation occurs even earlier than protein aggregation.Neuroinflammation in the CNS or peripheral immune cells may be more likely to induce protein deposition and exacerbate disease in some populations.
The immune system plays a crucial role in defending against and removing invading pathogenic microorganisms, maintaining tissue homeostasis and recovering from injury. Normally, immune response plays a neuroprotective role.
However, if normal ablative mechanisms fail to clear the inflammatory stimulus, the resulting persistent chronic inflammation in the CNS may trigger the release of neurotoxic factors, promoting disease progression.Therefore, understanding the molecules and signaling pathways involved in the CNS is vital for in-depth investigation of the mechanisms and therapeutic strategies of neurodegenerative diseases.
Key components of neuroinflammatory response
The following will explore the intricate web of CNS processes and components that constitute neuroinflammatory responses and contribute to the development of neurological disorders.
Cytokines and chemokines:
Cytokines and chemokines are signaling molecules that play a pivotal role in orchestrating the immune response during neuroinflammation. Among these,TNF-α, IL-1β, and interleukin-6 (IL-6) are well-established drug targets. Elevated levels of these pro-inflammatory cytokines are observed in neuroinflammatory conditions.
Microglia and macrophage markers:
Microglia and macrophages are the primary immune cells in the CNS.The activation of these cells is a hallmark of neuroinflammation. Researchers use antibodies such as CD11b, CD68, and Iba1 to label and study these cells in tissue sections and culture systems. These antibodies are essential for comprehending the dynamics of microglial and macrophage activation and their contribution to neuroinflammation.
Toll-like receptors (TLRs):
Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs).TLRs play a crucial role in the induction of innate immunity, and their modulators are potential drug targets.
Anti-inflammatory cytokines:
While pro-inflammatory cytokines drive neuroinflammation, anti-inflammatory cytokines like IL-10 and TGF-β counterbalance this response. Anti-inflammatory cytokines exert their anti-inflammatory effects by inhibiting the production of pro-inflammatory cytokines, as well as preventing antigen presentation blocking major histocompatibility complex (MHC) class II expression and co-stimulatory molecules such as CD80/CD86.
Cellular signaling pathways:
Cellular signaling pathways, such as the NF-κB and MAPK pathways along with crucial regulators such as TREM-2 are central to the regulation of neuroinflammation. Cell signaling pathways regulate neuroinflammation by modulating the expression of astrocyte chemokines and pro-inflammatory cytokines.Small molecule inhibitors targeting key signaling molecules are actively studied as potential therapeutics.
Biomarkers:
Biomarkers are critical for diagnosing and monitoring neuroinflammatory diseases. Biomarkers of neuroinflammation mainly refer to the specific expression of transcription factors,enzymes, cytoskeletal proteins and receptors by neurons and glia. Specific proteins, such as glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and Clusterin (TRPM2) can serve as biomarkers. In addition, AD biomarkers include growth factors (BDNF, NGF, VEGF), microglia inflammation markers (YKL40), and astroglial injury markers (GFAP), which are very important for early diagnosis of AD.
Emerging 3D models for neuroinflammation research
Since the inception of neuroscience, primary cells, immortalised cell lines and animal models have been vastly used as model organisms. A more recent trend is the use of organoids.
Specifically, neural organoids have emerged as invaluable tools in the study of neuroinflammation. These three-dimensional miniaturised brain models are cultivated from pluripotent stem cells by using various cytokines and growth factors such as BDNF, NGF, BFGF, CNTF, EGF, IGF and TGF-β, offering a unique platform to investigate the complexities of neuroinflammatory responses within a physiologically relevant context.
Pro-inflammatory cytokines such as TNF-α and IL-1β can be introduced to organoids to simulate infections to mimic the pathological conditions of the central nervous system. This enables the study of microglial activation, immune cell infiltration, and the impact of neuroinflammation on neural cells within a controlled environment.
Brain organoids provide a valuable bridge between traditional in-vitro cell culture models and in-vivo animal models, offering insights into the intricate cellular and molecular interactions underlying neuroinflammation and its role in neurological disorders. Sino Biological has developed a comprehensive range of bioactive recombinant cytokines from various species,such as human, mouse, cynomolgus, rhesus, rat, and canine, supporting research on neurodegenerative diseases (Figure 3).
Conclusion
Neuroinflammation is an inflammatory response within the CNS that is associated with a variety of neurodegenerative diseases. An in-depth exploration of the key components and mechanisms involved in neuroinflammation is critical for the treatment of neurodegenerative diseases.
Neuroinflammation research has made significant strides in recent years, partially attributed to the availability of high-quality bioreagents including recombinant proteins and antibodies which have enabled researchers to unravel the complexities of neuroinflammatory processes and identify promising drug targets. As the field continues to progress, Sino Biological, a global provider of bioreagents for biomedical research, remains providing the critical tools needed to advance neurodegenerative research, including a comprehensive collection of high-quality recombinant proteins and antibodies that represent therapeutic targets for neurodegenerative diseases, such as Alzheimer's disease, supporting groundbreaking discoveries and the development of targeted therapies for neuroinflammatory disorders.
