In order to effectively treat a disease, understanding its true underlying mechanism is essential (1). Unfortunately, for many chronic diseases, these mechanisms are not fully understood, which leads to a reliance on symptom-based management. Chronic rhinitis is one such disease (2). It refers to inflammation of the nasal mucosa that persists for a minimum of 12 weeks each year (3). Allergic rhinitis (AR) and non-allergic rhinitis (NAR) are two well-recognized subgroups of rhinitis (4).

The pathogenesis of chronic rhinitis is linked to immune mediators, environmental, genetic, and epigenetic factors. However, the available data is insufficient to draw definitive conclusions about the involvement of these factors particularly in AR (5). The available data have focused on the role of environment, genetics, and epigenetics in the pathogenesis of AR. The development of AR in individuals with atopic tendencies is believed to be strongly influenced by their exposure to various external environmental factors (6). Other than environmental factors, various genes associated with immune-related diseases, such as allergic and autoimmune disorders, are also involved (7).

The prevalence of AR varies among studies due to the lack of an acceptable definition for both conditions (8, 9). A review by Savoure et al. reported a wide range of prevalence, varying from 1% to 63% from 184 studies. The overall median prevalence rates of unspecified rhinitis, and AR, were 29.4% and 18.1%, respectively (9). The severity of chronic rhinitis, particularly AR symptoms, is associated with lower quality of life. A large Spanish cohort study concluded that AR symptoms have a considerable impact on the quality of life and sleep quality for all patients with AR (10).

However, despite well-defined clinical phenotypes of chronic rhinitis, the underlying pathophysiological mechanism, particularly with reference to the involvement of cytokines, genetic, and environmental factors, is still not fully understood (2). The significance of cytokines in AR is considered more significant among these factors. Cytokines possess roles that depend on the context and determine their usual physiological function. However, when cytokine pathways become dysregulated or chronically activated, they can disrupt the equilibrium of tissues, moving away from a state of balanced stability toward immunopathology associated with disease (11). The aim of the review was to give updated information on the pathogenesis of AR at the molecular level, with an emphasis on the role of cytokines in adults aged 18 years and above. Additionally, we investigated the impact of genetic and environmental factors in the pathogenesis of AR.

On May 02, 2023, a literature search was conducted based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search included relevant articles published between 2018 and 2023 in PubMed, Scopus, Wiley online library, and Google Scholar. Keywords such as Rhinitis, Chronic rhinitis, Allergic rhinitis, Non-Allergic Rhinitis, Pathophysiology, Etiology, Mechanism, Environmental factors, Epigenetic factors, Inflammatory Mediators, Inflammatory Biomarkers, Cytokines, Interleukin, Interferon, Chemokines, and Immune mediators were used in various combinations. The searches were conducted separately for each primary database using Boolean operators (AND) and (OR) in combination with Medical Subject Subheadings (MeSH) terms and key text words.

Our inclusion criteria include controlled trials that investigated the role of cytokines, genetic factors, and environmental factors in the pathogenesis of AR. Experimental or animal studies, non-English language studies, non-peer-reviewed studies, conference abstracts, papers, letters, and unpublished manuscripts were excluded. Likewise, studies that investigated the pathogenesis for coexistence of AR with other diseases were also excluded.

The potential studies were initially screened based on their abstracts and article titles. Subsequently, full-text articles of potential studies were evaluated by two independent researchers. Any discrepancies were discussed until a consensus was reached to ensure the accuracy of the research. We utilized descriptive statistics, such as mean and median, to obtain summary measures.

Chronic rhinitis, and AR in particular, is a major global health concern that affects approximately 400 million people worldwide. The prevalence of AR has been on the rise due to increased urbanization and exposure to environmental pollutants, which are believed to be among the leading causes of the disease. Developing effective therapies for chronic rhinitis requires a thorough understanding of its complex pathophysiology, including various contributing factors (1). Therefore, it is essential to review the complex pathogenesis of AR, considering multiple factors to identify potential drug targets for successful treatment.

Although literature reviews on AR are available, many of them are focused on either single pathology or based on a single pathogenic factor only (29, 30, 31). Our systematic review, on the other hand, takes a comprehensive approach to understand the pathogenesis of AR by considering multiple factors. This is one of the first reviews to adopt such a comprehensive approach. Our selected studies exhibit heterogeneity; therefore, a meta-analysis could not be performed. However, the broad overview of multiple factors in the pathogenesis of chronic rhinitis offers detailed information for researchers to understand its complex mechanism.

In our study, we have identified several cytokines that were reported in the included studies for their involvement in the pathogenesis of AR. The findings from the studies indicate that individuals with AR tend to have elevated levels of certain immune mediators such as CCL3, RvE1, LTB4, CD4+ T cells, IL-10, IL-6, IL-17, IL-22, and TGF-β, but reduced levels of the RvE1 and RvD1 ratio to LTB4, Th1 and Th17 subsets with chemokine receptors, and IFN-γ (13–17).

The role of Cytokines and Chemokines was described in various previous studies. AR is categorized as a type 2 inflammation mediated disease. The pathology of AR involves interleukins 4, 5, and 13, which play significant roles (32). The type 2 inflammatory response is provoked by both the innate immune system, which is activated by pollutants or viral or fungal infections and involves type 2 innate lymphoid cells (ILC2), and the adaptive immune system, which is stimulated by allergen exposure and involves type 2 T-helper (Th2) cells. Both ILC2 and Th2 cells release type-2 cytokines like interleukin IL-4, IL-5, and IL-13, playing diverse roles in the inflammatory cascade. IL-4 and IL-13 cause B-cell class switching and IgE production, provoke the discharge of pro-inflammatory substances, disrupt barriers, and encourage tissue remodeling. In addition, IL-13 prompts an increase in goblet cells leading to excess mucus production (33, 34).

Furthermore, there are indications that the pathophysiology of AR may encompass other pathways, specifically involving the regulation of Th2 cytokine responses by cytokines expressed in the epithelial cells. These cytokines include thymic stromal lymphopoietin, IL-25, and IL-33 (33). In addition to IL-4, IL-5, IL-13, IL-25, and IL-33, a range of other immune mediators contribute to the pathophysiology of AR. In the case of viral infections, elevated levels of various inflammatory cytokines, including IL-1β, IL-6, IL-7, IL-17, IFN-γ, IL-8, TNFα, and GM-CSF are observed, alongside IL-4 and IL-5. Similarly, during the allergy season, the levels of IL-4 and IL-10 decrease in nasal fluid. However, both cytokines demonstrate an increase in concentration 5 h after a nasal allergen challenge conducted outside the allergy season (35). We have also found a decrease in Th17 levels, which is in line with a previous review conducted by Fan et al., suggesting a negative correlation between Th17 and the occurrence of AR. The proposed mechanism is that regulatory B cells play a role in inhibiting the differentiation and proliferation of primary T cells into Th17 cells by facilitating the release of IL-10 and IL-35. As a result, this leads to a reduction in Th17 cells, a decrease in IL-17 secretion, and the alleviation of symptoms in individuals with AR (36).

Chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein 1-alpha (MIP-1-alpha), is a protein that in humans is encoded by the CCL3 gene and plays a role in inflammatory responses through binding to the receptors CCR1, CCR4 and CCR5 (37). CCL3 stimulates the movement of monocytes and T lymphocytes, although its impact varies among different T cell subsets. For instance, CCL3 primarily drives chemotaxis in B lymphocytes and activated CD8 T cells. This cytokine also prompts the chemotaxis of natural killer (NK) cells. Moreover, CCL3 acts as a chemoattractant for eosinophils and encourages basophils to discharge histamine. Additionally, CCL3 triggers the expression of ICAM-1, the degranulation of mast cells, and the production of tumor necrosis factor alpha (TNF-a), IL-1, and IL-6 (38). In their 2020 study, Berghi and colleagues discovered a notable elevation in the average serum CCL3 levels among patients suffering from Allergic Rhinitis (AR), compared to those in control groups. This finding can be associated with the significant function that CCL3 plays in sparking inflammation in cases of AR.

Endogenous lipid mediators known as Resolvins, specifically Resolvin E1 (RvE1) and Resolvin D1 (RvD1), are identified for their positive influence on resolving inflammation (39). RvE1 has the capability to bind to BLT-1, a receptor with a high affinity for leukotriene B4 (LTB4), which results in the suppression of LTB4-driven immune cell recruitment to inflamed areas. This binding action mitigates the LTB4-induced mobilization of immune cells to inflammation sites, indicating a competition between RvE1 and LTB4 for BLT-1 binding, with RvE1 functioning as a BLT-1 antagonist (40). In a 2020 study conducted by Lotfi and his team, they found that the lower ratios of RvE1 and RvD1 to LTB4 suggest an imbalance in the production of these mediators in AR patients. They suggested that the findings indicate a possibility that LTB4 might be dominating RvE1 in terms of BLT-1 binding, leading to impaired resolution of airway inflammation, and consequently contributing to the development of chronic airway inflammation. Overall, it appears that the increase in RvE1 is a critical action of the immune system to actively resolve allergic airway inflammation, though this effort remains insufficient. Notably, the study also found that serum levels of both IL-10 and TGF-β were significantly decreased in AR patients compared to healthy individuals, which is comparable to findings from a murine study conducted by Oner and associates in (41), where they demonstrated that RvE1 inhibited IL-10 synthesis by Th17 cells. Conversely, their study also revealed that RvE1 increased the production of TGF-β by dendritic cells.

Similar to the focus on cytokines, most of our studies also concentrated on examining the role of genetic factors, specifically in AR. The findings indicated an increase in the expression of allergy-related genes in the nasal mucosa, CD23 expression during T-B cell interaction, and TNF-induced HDAC11 expression. However, the IL1RL1 gene variants, namely rs72823628, rs950881, and rs3771175, were associated with a lower risk of developing AR (19–26). A review by Choi et al. reported multiple genetic and epigenetic factors, some of which were consistent with our findings (29). Lastly, regarding environmental factors, the selected study observed the effect of environmental factors in pathogenesis, and demonstrated an indirect relation between the expression of OCLN and CLDN7 to air pollution (27).

Our review has some limitations that should be addressed in future research. Firstly, the studies included in our review varied in terms of their objectives, methodology, and findings. Similarly, the studies focused on different sub-factors, making it difficult to compare their results. Therefore, future studies should focus on one aspect at a time to obtain more conclusive results. Furthermore, based on our findings, researchers should link these mechanisms to potential therapies for AR and mixed rhinitis.

Various factors, including immune mediators particularly cytokines, genetic, and environmental factors, are involved in the development of AR. However, the studies presented findings on different factors and sub-factors, making it challenging for us to compare their results. Therefore, future studies should focus on one aspect at a time to obtain more conclusive results. Additionally, researchers should connect these mechanisms to potential treatments for AR and mixed rhinitis based on our findings.