Neuroinflammation represents a fundamental component in the development and progression of a wide range of neurological disorders, including neurodegenerative diseases, psychiatric conditions, and cerebral injuries. This review examines the complex mechanisms underlying neuroinflammatory responses, with a focus on the interactions between glial cells and neurons. The dualistic role of neuroinflammation is further investigated, highlighting its ability to promote neuroprotection in acute phases while also contributing to neuronal injury and degeneration during chronic activation. This review also considers innovative therapeutic approaches designed to target neuroinflammatory processes, like drug-based treatments and immune-modulating therapies. A thorough understanding of the regulatory balance within neuroinflammatory networks is essential for the development of effective treatments for several neurological pathologies. Finally, this review provides an integrative summary of current evidence and highlights emerging directions in neuroinflammation research.

Aging is a complex, progressive, and irreversible biological process that entails numerous structural and functional changes in the organism. These changes affect all bodily systems, reducing their ability to respond and adapt to the environment. Chronic inflammation is one of the key factors driving the development of age-related diseases, ultimately causing a substantial decline in the functional abilities of older individuals. This persistent inflammatory state (commonly known as “inflammaging”) is characterized by elevated levels of pro-inflammatory cytokines, an increase in oxidative stress, and a perturbation of immune homeostasis. Several factors, including cellular senescence, contribute to this inflammatory milieu, thereby amplifying conditions such as cardiovascular disease, neurodegeneration, and metabolic disorders. Exploring the mechanisms of chronic inflammation in aging is essential for developing targeted interventions aimed at promoting healthy aging. This review explains the strong connection between aging and chronic inflammation, highlighting potential therapeutic approaches like pharmacological treatments, dietary strategies, and lifestyle changes.

Fibromyalgia represents a chronic pain pathology characterized by severe musculoskeletal pain, fatigue, disturbances in sleep, and cognitive issues. Despite its presence, the underlying mechanisms of fibromyalgia remain inadequately understood; however, recent investigations have suggested that inflammation could play a fundamental role in the pathophysiology of this condition. Several studies highlight elevated concentrations of pro-inflammatory cytokines, dysregulation of immune responses, and neuroinflammation in fibromyalgia patients. Furthermore, chronic low-grade inflammation has been proposed as a potential catalyst for the sensitization of pain pathways, which exacerbates the symptoms of fibromyalgia. Understanding the role of inflammation in this disease might open new avenues for therapeutic interventions while providing a more profound insight into the complex nature of this debilitating disorder. Although progress has been made, further research is needed to uncover the complexities involved. This review investigates the intricate relationship between inflammation and fibromyalgia, analyzing the evidence that supports the involvement of both peripheral and central inflammatory processes in the onset and persistence of the disorder.

TNF-α is a pro-inflammatory cytokine that plays a pivotal role in the regulation of immune responses. It is predominantly produced by activated macrophages, although other cell types, such as T lymphocytes and NK cells, also contribute to its secretion. TNF-α participates in various physiological processes, including cell proliferation and differentiation. Moreover, TNF-α has been implicated in the pathogenesis of numerous inflammatory and autoimmune disorders. Recent studies have highlighted the important role of TNF-α in neuropathic pain, a complex and frequently disabling condition caused by nerve injury or dysfunction. Increased TNF-α levels in the nervous system have been associated with the onset of neuropathic pain, contributing to neuronal sensitization and alterations in pain signaling pathways. This study supports the idea that TNF-α connects the immune system with the nervous system, thereby supporting our understanding of the neuroimmune interface of pain and bringing a potential treatment against neuropathic pain: targeting TNF-α. Anti-TNF-α antibody administration reduces pain behaviors and neuroinflammation in preclinical animal models. Simultaneously, clinical trials are evaluating the safety and efficacy of anti-TNF-α treatments, with preliminary results indicating promising outcomes in patients experiencing neuropathic pain. Here, targeting TNF-α goes beyond its conventional spectrum of inflammatory pathologies and initiates a new mechanism-based approach to defining neuropathic pain, thereby improving the quality of life of the individuals affected and bringing together an area of colossal unmet clinical need.

S100 proteins, a family of Ca²⁺-binding proteins, play numerous roles in cellular processes such as proliferation, differentiation, and apoptosis. Recent evidence has highlighted their critical involvement in neuroinflammation, a pathological hallmark of various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Among these proteins, S100B and S100A8/A9 are particularly implicated in modulating inflammatory responses in the CNS. Acting as DAMPs, they interact with pattern recognition receptors like RAGE and TLRs, triggering pro-inflammatory signaling cascades and glial activation. While low concentrations of S100 proteins may support neuroprotective functions, increased levels are often associated with exacerbated inflammation and neuronal damage. This review explores the dualistic nature of S100 proteins in neuroinflammatory processes, their molecular interactions, and their potential as biomarkers and therapeutic targets in neurodegenerative disease management.