"...Fallen through the cracks...": A Co-Produced Qualitative Exploration of Autistic Student Experiences at an Irish Higher Education Institution.

The oral cavity harbors diverse pathogenic and opportunistic microbial communities. Oral diseases encompass a broad spectrum of pathological conditions that affect both soft and hard tissues within the oral and maxillofacial regions, including periodontal disease, pulpitis, jaw injuries, peri-implantitis, oral mucosal diseases, and cleft lip and/or palate []. These diseases pose significant global public health concerns due to their high prevalence and the risk of progression into chronic infections if not appropriately managed []. Furthermore, accumulating evidence supports bidirectional associations between certain oral and systemic diseases. For instance, individuals with type 1 diabetes frequently exhibit elevated colonization levels of specific pathogenic microorganisms in their oral microbiota, such as Porphyromonas gingivalis, Prevotella intermedia, and Actinomyces species, which heighten their susceptibility to periodontal diseases []. Conversely, periodontal inflammation can adversely influence blood sugar control. In consequence, there is an urgent need to identify potential diagnostic and therapeutic targets for oral diseases. Macrophages are ubiquitously distributed throughout the body, residing in diverse anatomical locations, including the brain, liver, bone marrow, alveoli, and lymph nodes. Their precursors, monocytes, circulate in the bloodstream and occupy the bone marrow prior to differentiating into macrophages upon infiltrating various tissues. Macrophages execute multifaceted functions ranging from pathogen clearance and antigen presentation to orchestration of tissue repair and regeneration and the maintenance of microenvironmental homeostasis []. Numerous inflammatory diseases, such as pneumonia, intestinal inflammation, hepatitis, wound healing-associated inflammation, and periodontitis, have been closely associated with macrophage activity []. Macrophages are traditionally classified into M1 and M2 phenotypes, reflecting their distinct polarization states and functional profiles. However, it is crucial to recognize that macrophage phenotypes present in vivo are considerably more complex and often display mixed characteristics with monocytes. In functional terms, M1 macrophages are distinguished by their pro-inflammatory properties, while M2 macrophages exhibit anti-inflammatory activities. Recent advancements have led to a more refined categorization, with M2-like macrophages discernible as subtypes, namely, M2a, M2b, M2c, and M2d, contingent upon the nature of the stimuli []. Pro-inflammatory mediators such as lipopolysaccharide (LPS) and interferon-γ (IFN-γ) induce the polarization of M1 macrophages, eliciting the secretion of various pro-inflammatory cytokines and chemokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1α, IL-1β, and C-X-C motif chemokine ligand 9 (CXCL9) []. Conversely, M2 macrophages are activated by anti-inflammatory mediators such as IL-4 and IL-13, which stimulate the release of anti-inflammatory factors, including transforming growth factor-β (TGF-β), IL-10, C–C motif chemokine ligand 1 (CCL1), CCL17, and CCL18, participating in anti-inflammatory responses []. Functionally, classically activated M1 macrophages are primarily engaged in phagocytosis, MHC II antigen presentation, and the generation of reactive oxygen species []. In contrast, M2 macrophages promote extracellular matrix production, cell proliferation, and angiogenesis, thereby facilitating tissue remodeling and repair []. Consequently, the diverse phenotypes and secretory profiles of macrophages hold significant promise in the realm of oral disease prevention and treatment. Nonetheless, the precise mechanisms underlying macrophage polarization in oral pathologies, the intricate regulatory networks governing phenotypic plasticity, and the dynamic shifts in macrophage states throughout disease progression remain insufficiently elucidated. Within the oral microenvironment, a diverse array of cytokines, exosomes, resident microbiota, and their metabolic products converge to modulate macrophage phenotype and function. Accordingly, illustrating the polarization patterns and hidden molecular signaling pathways of macrophages in oral diseases is critical to deepen our understanding of immunopathogenesis and to establish a scientific rationale for the development of macrophage-targeted immunotherapeutic strategies. The present review aims to provide a comprehensive and systematic analysis of macrophage phenotypic profiles, regulatory pathways, and emerging interventional approaches in prevalent oral disorders, thereby advancing the modulation of the oral immune microenvironment.