Vitamin B12 (cobalamin) is an essential water-soluble micronutrient serving as a cofactor for key enzymes in one-carbon metabolism and mitochondrial energy production. Beyond its classical roles in hematopoiesis and neurological function, emerging evidence demonstrates that vitamin B12 has emerging immunometabolic roles. Through its role in methionine synthase-dependent one-carbon metabolism, cobalamin contributes to DNA synthesis, methylation reactions, and redox homeostasis—processes critical for the proliferation, differentiation, and function of both innate and adaptive immune cells. Deficiency has been associated with impaired immune responses and may contribute to altered susceptibility to infections and inflammatory disorders. Conversely, adequate cobalamin status restores methylation potential, mitochondrial bioenergetics, and redox homeostasis, potentially supporting T and B cell function and regulatory immune pathways, and modulating pro- and anti-inflammatory cytokine networks. Most evidence derives from deficient or high-risk populations, whereas immunomodulatory effects in vitamin B12-replete individuals remain uncertain. This review provides a comprehensive synthesis of mechanistic and clinical evidence, emphasizing vitamin B12 as a critical immunometabolic regulator and exploring its potential therapeutic applications in immune-mediated and inflammatory disorders.
Obesity is a major global health challenge, now recognized as a complex metabolic and inflammatory disorder characterized by excess adiposity and chronic low-grade inflammation. Adipose tissue functions as an endocrine organ, secreting adipokines that regulate metabolism and immune responses. Among these, Isthmin-1 (ISM1) has recently emerged as a novel adipokine with important metabolic and anti-inflammatory roles. ISM1 is widely expressed in adult tissues and is associated with central adiposity and metabolic dysfunction. It enhances glucose uptake via an insulin-independent PI3K/Akt pathway through integrin αVβ5 activation, promoting GLUT4 translocation. ISM1 also regulates lipid metabolism by inhibiting lipogenesis and stimulating fatty acid oxidation. Additionally, it exerts anti-inflammatory effects by suppressing NF-κB signaling and promoting macrophage polarization toward an anti-inflammatory phenotype. Exercise is known to improve adipokine profiles, insulin sensitivity, and inflammation, but its effects on ISM1 remain unexplored. This represents a critical gap in the literature. Understanding how different exercise modalities influence ISM1 could reveal new mechanisms underlying exercise benefits and support its potential as a biomarker or therapeutic target in obesity and metabolic disorders.
Human γδ T cells represent a minor subset of lymphocytes present in the peripheral blood. This lymphocyte subset is mainly localized within the mucosae of airways and gut. In the latter context, γδ T cells can represent a key immune cell subset involved both in regulating intestinal homeostasis and in responding to pathogens and colorectal carcinoma (CRC) growth. γδ T cell subsets such as the Vδ2+ respond to phosphate antigens produced by bacteria, while Vδ1+ cells can exert an immune response after mucosal stress stimuli. γδ T cells do not recognize as classical αβ+ T cells the peptide antigens in the context of major histocompatibility complex (MHC). γδ T cells may play a complementary role with αβ+ T cells in mucosal immunity at the gastrointestinal barrier. Colon γδ T cells can exhibit antitumor properties and regulatory functions. Indeed, human γδ T cell subsets present in the gut bear some activatory receptors, such as NKG2D and DNAX Accessory Molecule (DNAM)-1, leading to the elimination of CRC cells. By contrast, γδ T cells producing interleukin (IL)-17, transforming growth factor β, and amphiregulin show pro-tumor activity. This dual property of γδ T cells poses challenges for their use as an immunotherapeutic tool, while the MHC-independent recognition of antigens can support their use as off-the-shelf allogeneic cells.
Neuroimmune disorders are increasingly understood not as the consequence of dysfunction in isolated cell types, but as dynamic diseases shaped by coordinated transitions across interacting neural and immune cell states. This narrative review synthesizes current evidence showing how microglia, astrocytes, neural stem cells, vascular elements, and infiltrating peripheral immune cells shift between homeostatic, inflammatory, reparative, and disease-associated states in response to injury, infection, degeneration, and metabolic stress. We highlight how cytokine signaling, damage-associated molecular patterns, oxidative and metabolic stress, and transcriptional and epigenetic reprogramming reshape neuroimmune behavior across these cellular populations, thereby influencing inflammation, synaptic remodeling, tissue repair, and disease progression. By framing neurological disorders as state transition networks rather than static cellular abnormalities, this review integrates emerging insights from single-cell and spatial profiling with systems-level neuroimmunology and identifies cellular plasticity as both a mechanistic principle and a therapeutic opportunity. This perspective provides a unifying conceptual framework for understanding neuroimmune pathology in disorders such as Alzheimer’s disease, multiple sclerosis, stroke, and traumatic brain injury, while also pointing toward next-generation strategies that selectively modulate maladaptive cellular programs and promote regenerative neuroimmune states.
