Atopy is a spectrum of allergic hypersensitivity disorders, such as asthma, eczema, and allergic rhinitis, that has become a significant global health concern, with rising prevalence rates that particularly afflict industrialized nations [1]. The World Allergy Organization estimates that allergic diseases affect up to forty percent of the global population, placing a significant burden on healthcare systems and affecting the quality of life of affected individuals [2]. In the United States, asthma alone affects more than 25 million individuals, while conditions such as eczema and allergic rhinitis further contribute to this expanding healthcare challenge. The increasing prevalence of these conditions is likely due to a combination of genetic susceptibility, environmental factors, urbanization, dietary changes, and lifestyle shifts, all of which contribute to the complex pathophysiology of atopic diseases [3].

Atopic conditions persist and can be crippling, resulting in a substantial decline in the standard of living for those affected. For example, patients with asthma often experience persistent respiratory symptoms, reduced physical activity, and frequent exacerbations that can result in hospitalization [4]. Individuals with eczema and allergic rhinitis often experience chronic itching, discomfort, and sleep disturbances, which can lead to emotional distress and a reduced ability to participate in daily activities [5]. These conditions frequently collide, resulting in a cumulative burden that amplifies their impact on both patients and healthcare systems.

Atopic diseases are characterized by a dysregulated immune response, with a predominant presence of Th2 cells, elevated IgE production, and persistent inflammation. The specific molecular mechanisms for atopy are described in Fig. 1 below. A similar cascade primarily governed by release of immunomodulating proteins (interleukins) is also observed in allergic rhinitis [6,7] and allergic asthma conditions [8,9]. The dysregulation of the system is driven by a complex interplay of genetic, environmental, and immune factors, leading to a state of chronic inflammation that perpetuates disease progression [10]. Current therapeutic approaches for atopic diseases primarily emphasize symptom management and encompass the utilization of corticosteroids, antihistamines, bronchodilators, and allergen-specific immunotherapy [11]. Although these treatments are effective for many patients, they have limitations. Corticosteroids, for example, can have significant side effects, including osteoporosis, hypertension, and growth suppression in children. Moreover, the efficacy of these treatments may fluctuate, and certain patients may not exhibit a satisfactory response, particularly in cases of a severe or refractory nature [12]. This has led to increased interest in novel therapeutic approaches, such as photobiomodulation (PBM), which offers better control of symptoms with fewer side effects.

Figure 1. Illustrates the intricate immune network involved in the pathogenesis of atopic dermatitis. Upon allergen exposure, keratinocytes release thymic stromal lymphopoietin, triggering a cascade of events involving dendritic cells and innate lymphoid cells. This cascade leads to the release of various interleukins, proteases, and signaling proteins, ultimately activating T cells into different subsets, culminating in an allergic response.
Adapted from the article of Kim et al. (Int J Mol Sci 2016;17:1234) [15].

PBM is a promising therapeutic modality, particularly in the context of inflammation and immune-mediated diseases. PBM involves the utilization of low-level light in the near-infrared (NIR) spectrum, which exerts biological effects at the cellular and molecular levels [13]. The lower intensity of PBM makes it a noninvasive and nonhazardous alternative to high-intensity laser treatments. PBM has been demonstrated to reduce inflammation, promote tissue repair, and modulate immune responses in various experimental models and clinical studies [14]. The potential of PBM in the treatment of atopic diseases is highly compelling, given its capacity to target crucial immune pathways that are dysregulated in these conditions. This review provides a detailed analysis of the molecular mechanisms by which PBM exerts its therapeutic effects, with a focus on its potential application in atopy. Furthermore, significant experimental studies are discussed, highlighting the effects of PBM on immune responses in atopic conditions and providing a thorough understanding of its therapeutic potential.

PBM exerts its effects through the interaction of light photons with cellular chromophores, which leads to a cascade of biochemical and molecular events that influence cellular function. The primary chromophore associated with PBM is cytochrome c oxidase (CCO), an indispensable enzyme within the mitochondrial respiratory chain [15]. CCO plays a significant role in the production of cellular energy by facilitating the transfer of electrons from cytochrome c to molecular oxygen, thereby facilitating the synthesis of adenosine triphosphate (ATP) [16]. Upon absorption of light in the 600-950 nm range, CCO undergoes a conformational change that enhances mitochondrial electron transport, thereby increasing ATP production. This enhanced mitochondrial activity is critical for energy-dependent cellular processes, including those involved in tissue repair and immune modulation.

PBM also influences the levels of reactive oxygen species (ROS), which are important secondary messengers in various signaling pathways. Excessive ROS can lead to oxidative stress and cellular damage, but they also play essential roles in regulating cellular processes, including cell proliferation [17]. PBM-induced ROS production is tightly regulated, leading to the activation of redox-sensitive transcription factors such as nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 controls the expression of genes involved in the detoxification of reactive intermediates, and the maintenance of redox equilibrium is what Nrf2 does in the antioxidant response [18]. By increasing the cellular antioxidant capacity, Nrf2 activation by PBM helps to reduce oxidative stress and mitigate the chronic inflammation characteristic of atopic conditions.

Calcium ion (Ca²⁺) signaling is another critical pathway influenced by PBM. CCO and other chromophores can absorb light and trigger the opening of ion channels in the mitochondrial and plasma membranes, resulting in an influx of Ca²⁺ into the cytoplasm. An increase in the intracellular Ca²⁺ concentration activates several Ca²⁺-dependent signaling pathways, including those mediated by protein kinase C and calmodulin [19,20]. These pathways regulate a broad range of cellular processes, from gene expression and enzyme activity to the modulation of immune cell function. In the context of atopy, Ca²⁺ signaling plays a significant role in the activation and differentiation of T cells, mast cells, and other immune cells, rendering it a crucial target for PBM-mediated immunomodulation [21].

PBM has also been shown to exert significant effects on transcription factors that regulate inflammatory and immune responses. One of the most extensively studied effects is the inhibition of nuclear factor-kappa B (NF-κB), a transcription factor that regulates the expression of proinflammatory cytokines, chemokines, and adhesion molecules [22]. NF-κB is activated in response to various stress signals, including cytokines, pathogens, and oxidative stress, and plays a central role in coordinating the inflammatory response. By inhibiting NF-κB, PBM reduces the production of these inflammatory mediators, thereby attenuating the chronic inflammation that characterizes atopic diseases [23]. This is particulary true when using the red (600-810 nm) and the NIR (810-1,064 nm) wavelengths of light. As described by previous literature [24-26], red and NIR light can trigger cellular responses by interacting with mitochondria and ion channels respectively. Red light, absorbed by CCO, boosts energy production increasing ROS and ATP levels. NIR light can activate light-sensitive ion channels, elevating Ca²⁺ levels. These elevated levels can influence NF-κB to counteract inflammation. Furthermore, PBM has been demonstrated to increase the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, which promotes cell survival, proliferation, and anti-inflammatory responses [27]. PBM modulates these signaling pathways, which provides a mechanistic basis for its potential therapeutic effects on atopic disorders.

The effects of PBM on these cellular and molecular pathways are not limited to the immune system. PBM has also been demonstrated to influence the behavior of other cell types involved in the pathogenesis of atopic diseases, including epithelial cells, fibroblasts, and endothelial cells [26]. For example, it has been reported that PBM enhances the repair of damaged epithelial barriers, which are frequently compromised in conditions such as atopic dermatitis and allergic rhinitis. PBM helps increase the number of epithelial cells and reduce the number of allergens and pathogens that can cause inflammation. PBM can also modulate the activity of fibroblasts, which play a key role in tissue remodeling and fibrosis [28,29]. By regulating fibroblast proliferation and collagen production, PBM has the potential to prevent the onset of fibrotic lesions that are characteristic of chronic atopic conditions. Fig. 2 shows a general summary of the effects exerted by PBM at the cellular level to mitigate expression of proinflammatory cytrokies when tissues are under inflammatory conditions.

Figure 2. Red light, specifically between 600 and 810 nanometers, is absorbed by cytochrome c oxidase (CCO) within the mitochondria. This absorption displaces nitric oxide (NO), activating CCO and creating a proton gradient. This process leads to increased levels of calcium ions (Ca²⁺), reactive oxygen species (ROS), and adenosine triphosphate (ATP). Near-infrared (NIR) light, ranging from 810 to 1,064 nanometers, activates light-sensitive ion channels, also boosting Ca²⁺ levels. ROS, ATP, and Ca²⁺ have been shown to affect NF-κB to counteract inflammatory conditions.
Adapted from the article of Kitchen et al. (Int J Mol Sci 2022;23:5221) [24].

PBM has demonstrated significant potential in regulating these immune responses, providing a novel approach for treating atopic disorders. The suppression of proinflammatory cytokine production is one of the primary effects of PBM on the immune system. Cytokines such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) are critical mediators of inflammation in atopic conditions, driving the recruitment and activation of immune cells. Cytokines play a role in promoting the differentiation and activation of Th2 cells, which are central to the pathogenesis of atopic diseases [30,31]. Studies have indicated that PBM can inhibit the expression of these proinflammatory cytokines, thereby reducing the inflammatory milieu that contributes to disease progression. By reducing the production of these cytokines, PBM aids in reducing the chronic inflammatory state associated with atopy, potentially leading to a reduction in symptoms and disease severity.

In addition to suppressing proinflammatory cytokines, PBM can augment the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10). IL-10 is a potent immunoregulatory cytokine that plays an important role in limiting immune responses and preserving immune homeostasis. It acts by inhibiting the production of proinflammatory cytokines, downregulating the expression of major histocompatibility complex (MHC) class II molecules on antigen-presenting cells, and promoting the development of regulatory T cells (Tregs) [32,33]. The ability of PBM to increase IL-10 production suggests that PBM could be used to reduce allergic inflammation and promote immune tolerance in atopic individuals [34]. This shift toward a more balanced immune response could help mitigate the exaggerated Th2-reaction and reduce the overproduction of IgE characteristic of atopic diseases.

PBM also significantly affects the activity of mast cells, which are crucial effector cells in allergic reactions. Mast cells play a central role in the pathogenesis of atopic disorders by releasing histamine and other mediators that contribute to the symptoms of allergies, such as itching, swelling, and bronchoconstriction. The rapid release of preformed mediators stored in cytoplasmic granules is triggered by the cross-linking of surface-bound IgE with specific allergens, leading to the rapid release of mast cell degranulation [35,36]. The inflammatory response is further exacerbated by the production of newly synthesized mediators, such as leukotrienes and cytokines. The evidence suggests that PBM has the ability to stabilize mast cells, thereby reducing their degranulation and the subsequent release of proinflammatory mediators [25,37]. This effect could be especially helpful in managing allergic reactions and reducing the severity of atopic symptoms. By stabilizing mast cells and reducing histamine release, PBM has the potential to alleviate the acute inflammatory responses that characterize numerous atopic disorders.

In addition to its effects on mast cells, PBM has been shown to influence the function of other immune cells involved in atopic diseases, including T cells and dendritic cells. PBM has been reported to modulate the activity of T cells, promoting a shift from a Th2-dominated response to a more balanced Th1/Th2-reaction. This shift is critical for reducing the overactive Th2 response that drives IgE production and allergic inflammation [29]. Th1 and Th2 cells are distinct subsets of CD4+ T helper cells that produce different cytokines and mediate different types of immune responses. Th1 cells are associated with cellular immunity and the production of cytokines such as interferon-gamma, whereas Th2 cells are associated with humoral immunity and the production of cytokines [38]. In atopic diseases, the balance between Th1 and Th2 cells is skewed toward a Th2-dominated response, resulting in excessive production of IgE and allergic inflammation [39]. The ability of PBMs to restore this balance by promoting Th1 differentiation and inhibiting Th2 differentiation is an important aspect of their therapeutic potential.

Furthermore, PBM has the potential to enhance the functionality of Tregs, which play a pivotal role in sustaining immune tolerance and preventing excessive immune responses. Tregs are a specialized subset of CD4+ T cells that express the transcription factor FoxP3 and produce immunosuppressive cytokines such as IL-10 and transforming growth factor-beta (TGF-β) [40]. Tregs are essential for maintaining tolerance and preventing autoimmune diseases, as well as for regulating immune responses to allergens and pathogens [40]. In the context of atopic diseases, where immune tolerance is often compromised, the ability of PBM to promote Treg function could help to restore immune homeostasis and reduce the likelihood of allergic sensitization and chronic inflammation [41].

The impact of PBM on dendritic cells, which are crucial antigen-presenting cells involved in initiating and regulating immune responses, further supports its potential as a therapeutic approach for atopic diseases. The differentiation of T helper cell subsets is influenced by dendritic cells, which capture and process antigens, including allergens, and present them to T cells. PBM modulates dendritic cell function, including the expression of surface molecules such as MHC class II and costimulatory molecules, which are essential for T cell activation [42,43]. By influencing dendritic cell function, PBM may help skew the immune response away from a Th2-dominated profile and promote a more balanced immune response that is less likely to lead to allergic sensitization.

A growing body of experimental evidence underscores the relevance of PBM in the treatment of atopic diseases. These studies have employed diverse animal models and in vitro systems to investigate the impact of PBM on immune responses and inflammation in the context of atopy, thereby providing crucial insights into its mechanisms of action and therapeutic potential. The specifics for the experimental models or PBM parameters are indicated in Table 1.

Table 1 . Results of research on the effects of photobiomodulation on various atopy-related models

Model	PBM parameter	Key finding	Conclusion	Reference	Potential clinical application
Mouse model of allergic asthma	610 nm, 1.7 mW/cm2, 2.9 J/cm2, 1.6 cm2 surface area	Reduced airway hyperresponsiveness, eosinophilia, Th2 cytokines, and IgE; modulated GATA3 and T-bet expression	PBM may shift the Th2-dominated immune response in asthma, offering a new treatment approach	[44]	Development of laser and LED devices for photobiomodulation treatment of nasal passages Development of cell based treatment for asthma and allergic rhinitis Development of drug treatment combined with light irradiation for treating allergic asthma and allergic rhinitis
Mouse model of allergic rhinitis	660 nm, 33.3 W/cm2, 5.35 J/cm2, 2.8 cm2 surface area	Reduced nasal symptoms and histamine levels; decreased mast cell activation and FcεRI expression	PBM stabilizes mast cells and attenuates allergic responses in allergic rhinitis	[45]
Mouse model of atopic dermatitis	650 nm, 50 mW, 3-8 J/cm2	Reduced skin inflammation, mast cell infiltration, and pro-inflammatory cytokines; enhanced IL-10 production	PBM promotes immune modulation and skin repair in atopic dermatitis	[46]	Development of wearable LED devices for management and treatment of atopic dermatitis Development of drug treatment combined with light irradiation for treating atopic dermatitis
In vitro study on human PBMCs	606 and 808 nm, 0.71 W/cm2, 5 J/cm2, 0.028 cm2 surface area	Reduced Th2 cytokine production, increased IL-10, and modulated GATA3 and FoxP3 expression	PBM may promote regulatory T cell responses, offering potential therapeutic benefits for atopic dermatitis	[47]	Integration of laser or LED irradiation in blood processing devices such as dialysis machines to prevent or manage atopic dermatitis

One notable study by Park et al. [44] investigated the effects of PBM on a murine model of allergic asthma. Airway hyperresponsiveness, inflammation, and remodeling are some of the characteristics of allergic asthma. A well-established allergen that induces an asthmatic response characterized by eosinophilic infiltration, mucus hypersecretion, and airway hyperresponsiveness was used in the murine model of allergic asthma used in this study. The effects on airway inflammation and immune responses were assessed after the mice were treated with PBM at specific wavelengths and dosages, and the effects on the mice were assessed. Further analysis revealed that PBM therapy significantly reduced airway hyperresponsiveness, eosinophilic infiltration, and mucus production, which are key features of allergic asthma. This study also strongly suggested that PBM altered the expression of transcription factors such as GATA3 and T-bet, which are crucial regulators of Th2 and Th1 differentiation, respectively. GATA3 is important for Th2 cell differentiation and the production of Th2 cytokines, whereas TGF-β is important for Th1 cell differentiation and the production of IFN-γ. By modulating the expression of these transcription factors, PBM effectively shifts the immune response from a Th2-dominated profile to a more balanced Th1/Th2 response, thereby reducing the severity of allergic asthma.

Another significant study by Kim et al. [45] focused on the effects of PBM in a murine model of atopic dermatitis, a common inflammatory skin condition characterized by eczematous lesions, pruritus, and a Th2-dominated immune response. This study used a murine model of atopic dermatitis to induce a chronic inflammatory response in the skin that closely resembled human atopic dermatitis. Mice were treated with PBM at specific wavelengths and power densities, and the effects on skin inflammation and immune responses were evaluated. The findings demonstrated that PBM significantly reduced skin inflammation, as evidenced by a reduction in erythema, edema, and epidermal thickness. Histological analysis revealed a reduction in mast cell infiltration and degranulation in skin lesions, as well as a decrease in the levels of proinflammatory cytokines such as IL-6 and TNF-α. The production of anti-inflammatory cytokines such as IL-10, which plays a key role in limiting inflammatory responses and promoting tissue repair, was shown to be enhanced by PBM. These results suggest that PBM may be able to modulate the immune response and promote skin barrier repair in atopic dermatitis, providing a potential therapeutic approach for managing this condition.

A further study by Schapochnik et al. [46] investigated the impact of PBM on mast cell activity in a murine model of allergic rhinitis. The symptoms of allergic rhinitis include nasal congestion, sneezing, and itching, driven by mast cell activation and histamine release in response to allergens. In this study, mice were exposed to house dust mite extract, which causes a nasal allergic response that results in sneezing, nasal rubbing, and increased histamine levels. Mice were treated with PBM at various wavelengths and power densities, and the effects on nasal symptoms and immune responses were assessed. The results indicated that PBM significantly reduced nasal symptoms, including sneezing, nasal rubbing, and histamine levels in the nasal lavage fluid. Flow cytometric analysis revealed a decrease in the percentage of activated mast cells in the nasal mucosa, along with a reduction in the expression of FcεRI, the high-affinity IgE receptor. FcεRI is essential for IgE-mediated mast cell activation and degranulation, and its downregulation by PBM suggests a mechanism by which PBM can stabilize mast cells and reduce allergic responses in allergic rhinitis. These findings indicate that PBM has the ability to inhibit mast cell activation and histamine release, providing a novel therapeutic approach for managing allergic rhinitis.

Furthermore, in vitro experiments have provided further insights into the cellular mechanisms underlying the effects of PBM on immune cells. For example, a study by Sá et al. [47] investigated the effects of PBM on human peripheral blood mononuclear cells (PBMCs). PBMCs are a heterogeneous population of immune cells that include lymphocytes (T cells, B cells, and natural killer cells) and monocytes, and they play crucial roles in mediating immune responses. The present study examined the effects of PBM on cytokine production and gene expression in PBMCs at specific wavelengths and power densities. This study demonstrated that PBM treatment resulted in a significant decrease in the production of Th2 cytokines, such as IL-4 and IL-13, which play pivotal roles in the pathogenesis of atopic dermatitis. 13 helps B cells generate IgE, strengthens adhesion molecules on endothelial cells, and helps eosinophils become involved. The decrease in these cytokines by PBM suggests a potential mechanism for modulating the immune response in atopic dermatitis. Furthermore, PBM could increase the production of IL-10, suggesting that PBM could promote a shift toward a Treg phenotype. The present study also revealed that PBM altered the expression of transcription factors involved in T cell differentiation, including GATA3 and FoxP3. The development and function of Tregs are dependent on FoxP3, which plays a critical role in maintaining immune tolerance and preventing excessive immune responses. The capacity of PBM to increase FoxP3 expression and increase Treg activity further supports its potential as a therapeutic approach for addressing immune dysregulation in atopic conditions.

The importance of PBM as a therapeutic modality for atopic disorders is emphasized by its ability to modulate key immune pathways involved in the pathogenesis of these conditions. Although preclinical studies provide promising data, the translation of these findings into clinical practice requires careful consideration of several factors.

One of the primary obstacles in implementing the PBM for atopic conditions is the optimization of treatment parameters. PBM is highly dependent on factors such as wavelength, power density, and treatment duration. Standardizing these parameters across different studies and clinical settings is essential to achieve consistent and reproducible outcomes. The creation of guidelines and protocols for the utilization of PBM in the treatment of atopy will be imperative for the successful implementation of this therapy in clinical settings. This includes determining the optimal dose of light energy required for therapeutic effects, as well as identifying the most effective wavelengths for targeting specific immune pathways.

Furthermore, while PBM has been found to be harmless in numerous studies, its long-term effects, particularly when applied to ongoing treatment for atopic disorders, require thorough examination. The risk of tissue overheating, unintended stimulation of proinflammatory pathways, and the possibility of reduced efficacy with prolonged use are all possible concerns. To assess the safety and efficacy of PBM in treating atopic disorders, as well as to identify any potential risks associated with chronic use, long-term clinical trials are needed. These studies should also investigate the effects of repeated PBM treatments over an extended period, as atopic diseases are chronic conditions that often require long-term management.

Future research should prioritize large-scale clinical trials to assess the safety and efficacy of PBM in treating atopy. The objectives of these studies should be to establish optimal treatment parameters, investigate the underlying mechanisms underlying the immunomodulatory properties of PBM in greater detail, and evaluate the long-term advantages and drawbacks of PBM treatment. More sophisticated devices that allow for precise control of treatment parameters and targeted delivery of light could enhance the therapeutic potential of PBM for atopic conditions. Future developments in PBM technology, such as the development of wearable PBM devices or the integration of PBM with other therapeutic modalities, could further expand its clinical applications.

Collaboration among researchers, healthcare professionals, and industry partners is needed for the integration of PBM into clinical practice for the treatment of atopy. As our understanding of the mechanisms underlying PBM continues to grow, there is potential for the development of new and innovative PBM therapies that can provide effective relief for patients with atopic disorders. These therapies could offer a much-needed alternative to conventional treatments, particularly for patients who do not respond adequately to existing therapies or who experience significant side effects.

Finally, the exploration of PBM as a preventive measure for atopic diseases is another avenue that warrants further investigation. The capacity of PBM to regulate immune responses and reduce inflammation suggests its potential as a preventive treatment for individuals at high risk of developing atopic conditions, such as those with a family history of atopy or early indications of allergic sensitivity. Future research could investigate the use of PBM in preventing the onset or progression of atopic diseases, thereby reducing the overall burden of these conditions on individuals and healthcare systems.

PBM emerges as a promising therapeutic approach for atopic disorders by regulating immune responses and reducing inflammation. PBM’s influence on key immune pathways, such as suppressing pro-inflammatory cytokines, enhancing anti-inflammatory cytokines, and stabilizing mast cells, provides a mechanistic basis for its potential therapeutic effects. Preclinical studies have shown PBM’s efficacy in reducing symptoms and modulating immune responses in atopic disorders, suggesting its potential as a valuable adjunct therapy. Further research is necessary to optimize treatment parameters, assess long-term safety, and evaluate PBM’s efficacy in large-scale clinical trials. Standardized protocols and guidelines are crucial for the successful implementation of PBM in clinical settings. As research advances, PBM holds the potential to become a significant tool in managing atopic disorders, offering patients a safe and effective alternative or adjunct to conventional therapies. This paper highlights the urgent need to explore innovative therapies such as PBM, especially given the increasing incidence of atopic disease. We may be able to develop more effective and sustainable treatment options that address the underlying immune dysregulation in atopic disorders by understanding and harnessing the mechanisms of PBM. As our understanding of PBM mechanisms and clinical applications continue to expand, it is hoped that this therapy may have a significant effect on the global burden of atopic diseases by providing novel advancements for prevention, treatment, and long-term management.

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Conceptualization: KW. Data curation: KW. Formal analysis: KW. Investigation: KW, AP. Validation: KW, AP. Visualization: AP. Writing-original draft: KW. Writing–review & editing: all authors.

Andrew Padalhin is an editorial board member of the journal but was not involved in the review process of this manuscript. Otherwise, there is no conflict of interest to declare.

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