Editorial: Intercellular communication in chronic neuroinflammatory diseases

Among the mediators of neuroinflammation, connexins (Cxs) have emerged as a major focus of research in the field of neuroinflammation, with studies highlighting mechanistic insights and therapeutic possibilities for targeting Cxs. Cxs are a diverse family of transmembrane proteins that form hemichannels, enabling communication between intracellular and extracellular spaces and supporting homeostasis in the CNS (Vicario and Parenti, 2022). The review by Denaro et al. Intercellular communication that contributes to homeostasis and regulation of immune responses in the CNS occurs through various mechanisms. In addition to direct cell-to-cell contacts mediated by gap junction-forming Cxs, inflammatory responses are regulated by systemic immune modulation and by autocrine and paracrine signaling via cytokines, chemokines, growth factors, extracellular vesicles and lipid metabolites (Decrock et al., 2015). In their minireview, Müller and Di Benedetto focus on microglial crosstalk with neurons and astrocytes, placing microglia at the center of neuroimmune communication. Microglia-released cytokines and chemokines influence neuronal activity and the release of gliotransmitters and cytokines from astrocytes, and other microglia, affecting downstream steps of inflammatory cascades. The paper covers different molecular and cellular mediators of neuroinflammation and summarizes recent discoveries on the interaction between peripheral immunity and intercellular communication in the CNS. The authors also describe therapeutic strategies for neuroinflammation, along with the challenges that must be addressed to develop effective therapies that preserve protective immune functions and avoid immunosuppression.Intercellular communication and inflammation are also affected by a number of intracellular processes that contribute to changes in the extracellular composition of nutrients, proteins, mitochondria, and extracellular vesicles. An example of such an intracellular process is autophagy, a conserved cellular degradation and recycling mechanism (Piletic et al., 2023). The manuscript by Potokar and Jorgačevski highlights the therapeutic potential of targeting autophagy and mitophagy in astrocytes, an area that has received considerably less attention than autophagy in neurons. Astrocytes are intricately involved in maintaining neuronal homeostasis and undergo phenotypic changes towards a reactive state during neurodegeneration. During inflammation, they release proinflammatory cytokines and, due to their strategic position at the blood-brain barrier, actively maintain its permeability, making them among the first CNS cells to encounter circulating drugs. The review summarizes possible modulators of autophagy and mitophagy, focusing only on those modulators that readily cross the blood-brain barrier.Research that combines experiments on isolated cells and cell lines with animal models exhibiting signs and symptoms similar to human neurodegenerative diseases is essential for understanding intercellular communication and inflammation in the nervous system. Selecting an appropriate model must be closely aligned with the pathophysiology of the disease or biological process under investigation. Hiroko et al.summarize the diversity of models used in studies of neurological disorders. Mouse models are the most widely used in biomedical research, as they share a high degree of genetic and physiological similarity with humans. In addition, zebrafish models are increasingly used, as certain features make zebrafish critical for investigating neurodegenerative diseases and potential treatment strategies. Comparative studies using these models can help identify candidate molecular factors with therapeutic relevance for promoting neural regeneration in mammalian neurological disorders. (Dendrou et al., 2015). Beyond the current diagnostic approaches, which rely primarily on clinical and radiological criteria, the authors aimed to identify new biomarkers of RR-MS. To this end, they focused on extracellular vesicles, specifically exosomes, which are known to modulate inflammatory responses in the CNS and have emerged as promising biomarkers and therapeutic targets in MS (Hasaniani et al., 2024). Their research is intriguing as it reveals altered lipid signatures in circulating exosomes of RR-MS patients and paves the way for further insights into disease mechanisms, as well as the development of diagnostic tools and therapeutic applications.