Nasal cancer shows the highest cancer risk among all cancer types observed in patients with a history of AR ( Table 1 ). Consistent with this finding, significantly increased immunoreactivity for TGF-β and TGF-β receptors was reported in the nasal mucosa of AR patients compared to the nasal mucosa of normal controls (65). Increased IL-1β and IL-6 levels (needed for TH17 differentiation) in nasal lavage was reported in AR patients following allergen challenge (66).

A study involving 423 asthma patients found that obese patients demonstrated more neutrophils in sputum and blood than nonobese patients (87). This result is consistent with two other studies (88, 89). In a large study that included 727 adult asthma patients, Todd et al. (90) found no statistically significant difference in sputum neutrophil count among five groups with increasing median BMI. However, in this study, the mean neutrophil count consistently increased with increasing BMI. A more recent study reports elevated blood neutrophils with a higher BMI in 166 adolescent asthma patients (91). In another recent study, the serum leptin level was higher in obese than in lean female mice. This study demonstrated that leptin/obR signaling (obR is the leptin receptor), plays an important role in the pathogenesis of obesity-related neutrophilic airway inflammation in females, by promoting M1 macrophage polarization (92). A recent review discusses the contribution of neutrophils to obesity-associated inflammation (93). It is also noted that obesity in non-asthmatic adolescents is associated with increased sputum mRNA expression of IL6, IL8, IL13, IL17, IL23, and IFN-γ (94).

In contrast to neutrophilic asthma, allergic rhinitis inflammation is mainly mediated by Th2 cytokines. Although allergic rhinitis patients demonstrate increased levels of Th17 cytokines as well (95), blood frequencies of Th17 cells in asthmatic children were reported to be statistically significantly higher compared to those in children with allergic rhinitis (96). This difference would likely increase if only children with neutrophilic asthma were included in this study. As a Th2 disease, the presence of IL-4 and IL-13 is needed for AR development. Allergic rhinitis is associated with IL-4 and IL-13 polymorphism (97), and dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to inhibit type 2 inflammation such as AR (98, 99). At the same time, high TGF-β levels which are essential for the development of neutrophilic asthma, inhibits the development of Th2 reactions (100), and hence suppress allergic rhinitis (see Figure 1 ). It must be noted that TGFβ is also produced by eosinophils (as well as epithelial cells, macrophages, and fibroblasts) (101). Yet, the increased levels of IL-1β in neutrophilic asthma (as indicated by Simpson et al. (38)) likely contribute to a more pronounced differentiation of Th17 cells with this phenotype. It was also reported that Th17/Treg homeostasis, but not Th1/Th2 homeostasis, is implicated in the exacerbation of human bronchial asthma (102), underscoring the role of neutrophils in airway inflammation. Collectively, the distinct association of asthma with long-term comorbidities can be primarily attributed to neutrophilic patients, due to the elevated circulatory levels of TGF-β, IL-1β and IL-6 in this type of asthma.

For simplicity, this study adopts a dichotomous model where high TGF-β activity in conjunction with IL-1β and IL-6 is linked to asthma, metabolic dysregulations, and an elevated risk of cancer, while it is inversely associated with the occurrence of AR. In contrast, low TGF-β activity (with or without the presence of IL-1β and IL-6 levels), are associated with the inverse effects. In previous publications, the binary classification of immune response as “high Treg” or “low Treg”, proved useful in elucidating the association of certain pathogens with cancer and the association of others with autoimmune diseases. It also explained why certain specific pathogens are involved in coinfections. The effectiveness or ineffectiveness of specific immune-modulating drugs in the treatment of autoimmunity and cancer was also clarified by this binary model (103). The binary Tregs classification was also found to be useful in predicting the efficacy or inefficacy of several immune-modulating drugs in the treatment of severe coronavirus disease 2019 (COVID-19) (104, 105). Since regulatory T cells are a major source of TGF-β, the “high TGF-β” or “low TGF-β” classification is closely related to the “high Treg” and “low Treg” classification.

A binary classification of immune responses aligns with the two pathways of nutrients metabolism used by eukaryotic living cells to utilize and store energy: oxidative phosphorylation (OXPHOS) and glycolysis. OXPHOS consists of two closely interconnected components: the electron transport chain, which in eukaryotes occurs in the mitochondria, and chemiosmosis. NADH and succinate, produced in the citric acid cycle, undergo oxidation, releasing energy used by ATP synthase to facilitate the formation of ATP (adenosine triphosphate). The process of glycolysis, on the other hand, occurs in the cytoplasm and produces 2 ATP molecules per glucose molecule. Pyruvate, the end-product of glycolysis, serves as fuel for OXPHOS. Under aerobic conditions, pyruvate enters the mitochondria for oxidation to acetyl CoA, initiating the tricarboxylic acid (TCA) cycle and OXPHOS, which can yield 36 ATPs per glucose molecule. Conversely, under anaerobic conditions, pyruvate is reduced to lactate, by lactate dehydrogenase A (LDH-A) in the cytoplasm. The resulting lactate is then excreted into the extracellular space through monocarboxylate transporters. Normal cells usually release energy for ATP synthesis through OXPHOS (with glucose and fatty acids as fuels). However, most cancer cells preferentially utilize glycolysis, even in the presence of oxygen, a phenomenon known as the Warburg effect (106). While the glycolytic pathway from glucose to pyruvate is less efficient in energy exploitation than OXPHOS, its rate is faster. Inflammatory cells, including Th1, Th17, CD8 T cells, and M1 macrophages, primarily use glycolysis for energy storage. On the other hand, immune cells associated with the anti-inflammatory arm of the immune system, such as Tregs, M2 macrophages, memory T cells, and resting microglia, rely predominantly on OXPHOS and fatty acid oxidation for ATP production (106, 107).

TGF-β has been associated with increased glycolysis in cancers (108–111) and osteoarthritis (112). In addition, as aforementioned, in the absence of IL-1β and/or IL-6, it induces immunosuppression. In fact, Gauthier et al. (113) recently demonstrated that TGF-β uncouples glycolysis and inflammation in macrophages. By enhancing the expression and activity of a glycolytic enzyme, TGF-β induced glycolysis in macrophages, but, at the same time, suppressed their pro-inflammatory cytokines.

Rates of glycolysis in the liver, in pancreas β cells, and in adipose tissue are increased in DM2 due to compensatory hyperinsulinemia (114). It was also reported that aerobic glycolysis is increased in CD4 T cells in asthma (115). Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils, relative to healthy controls. One source of lactate production in asthmatic patients were primary nasal epithelial cells (116). Taken together, elevated TGF-β levels and increased glycolysis are associated with asthma (especially neutrophilic asthma), with an increased risk of cancer, with obesity, with DM2, hypertension, and with insulin resistance.

No studies describing OXPHOS activity in AR could be found. However, atopic dermatitis, which is associated with a low-producer TGF-β1 cytokine genotype (117), exhibits high OXPHOS activity in nonlesional skin (118). On the other hand, TGF-β1 expression was found to be markedly enhanced in atopic dermatitis lesions (119). In agreement, a mouse model of lesional atopic dermatitis demonstrated metabolic shift toward enhanced anaerobic glycolysis (120). Urticaria shows lower serum TGF-β levels compared to normal levels, but the difference was not statistically significant (121). Mast cells, the primary cells involved in producing urticaria wheals (122), utilize the OXPHOS process as a crucial step for mast cell degranulation and cytokine synthesis (123, 124). The connection between TGF-β levels and cell metabolism extends beyond allergic diseases. Sepsis, for instance, is linked to elevated circulating levels of TGF-β (125, 126). In line with this, glycolysis is the primary pathway determining the allocation of energy to organ cells during sepsis (127). The levels of TGF-β are elevated in joint synovial fluid of rheumatoid arthritis (RA) patients (128, 129). Glycolysis is increased in fibroblast-like synoviocytes in RA (130, 131).

In the cancer context, elevated TGF-β levels reprogram macrophage metabolism toward the glycolytic pathway while simultaneously suppressing their pro-inflammatory machinery (113) and diminishing their anti-cancer efficacy. Within adipose tissue, TGF-β-associated glycolysis in macrophages contributes to low-grade inflammation (132), a characteristic feature of obesity (133). Thus, the effect of TGF-β on both cancer cells and adipose tissue is, at least partially, mediated by macrophages and potentially other immune cells.

This data is presented in Table 2 .

Regarding cancer initiation, high levels of glucose uptake observed in poorly differentiated different types of cancer reflect persistence of the glycolytic metabolism of stem cells in malignant cells that fail to fully differentiate (137). Biasing cancer stem cells’ metabolism toward the aerobic glycolytic pathway (the Warburg effect) drives their persistence in certain cancer types (breast cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, uterine endometrial) (138, 139). As discussed above, TGF-β induces glycolysis and, therefore, promotes self-renewal in these cancers. However, stem cells of other cancer types (glioma, glioblastoma. lung cancer, pancreatic ductal adenocarcinoma, and leukemia) have demonstrated OXPHOS as their preferred energy production process (138, 139).

A clear distinction must be drawn between the association and causality of events. To establish causality, it is necessary for a change introduced in one event to result in some observable change in the second event. Reverting to the previous discussions, efforts have been undertaken to examine the causal relationship between TGF-β signaling and asthma. This has been pursued by studying the impact of anti-TGF-β/Smad agents on airway inflammation. There are indications that the role of TGF-β changes along the course of asthma development. TGF-β seems to inhibit the development of asthma in the initial stage of the disease, however it supports and maintains established inflammatory asthma. This temporal change in the role of TGF-β was reflected in the work by Fredriksson et al. (140) who demonstrated a contrasting effect of rapamycin on asthma which was depended on the stage of the disease. Rapamycin is known to activate the TGF-β signaling (141–143). Airway inflammation in a murine model was attenuated when rapamycin was administered during the induction stage of asthma, while inflammation was induced when rapamycin was administered in established asthma. In addition, rapamycin induced airway hyperactivity (i.e., exacerbation of the disease) in moderate lymphangioleiomyomatosis (a rare and progressive lung disease leading to the blockage of airways and blood vessels) (144). Here rapamycin was administered to patients with established lung inflammation. When CD4(+) T helper cells engineered to produce latent TGF-β1 were transferred to OVA-sensitized SCID mice 1-2 days before the mice were re-challenged with ovalbumin (OVA), airway inflammation was attenuated (145). Similarly, when TGF-β-secreting bone marrow stroma cells were injected intravenously to mice with ragweed induced asthma at the time of the antigen challenge, they protected the mice from most asthma-specific pathological changes, including Th2 related inflammatory cytokines and immunoglobulins (146).

Conversely, when nintedanib, a TGF-β/Smad pathway inhibitor (147), was given orally once a day (started day 35) to OVA-sensitized mice, after the starting of repeated OVA challenge (started day 31), airway inflammation was ameliorated (148). Similarly, when anti-TGF-β antibodies were injected to OVA-sensitized mice 30 minutes before each OVA-challenge for seven days, airway inflammation improved (149). Here again, the anti-TGF-β agent was administered (for 6 days) to mice after repeated OVA challenges. Pirfenidone is an antifibrotic agent that inhibits the TGF-β/Smad pathway (150). When OVA-sensitized mice were put on pirfenidone diet started before OVA-rechallenge and extended into a period of OVA-rechallenges, the results were mixed: pirfenidone had no effect on airway hyper-responsiveness, however pirfenidone significantly reduced distal bronchiolar cellularity and proximal and distal bronchiolar mucin content (151).

The pro-inflammatory role of TGF-β in established asthma may be related to asthma highly inflammatory environment that includes high concentrations of IL-6 and IL-21 (152), which in mice induce Th17 differentiation in the presence of low levels of TGF-β (31, 153) (in human, the presence of IL-1β is also required (32)). Th17 cytokines, including IL-17, play a role in neutrophilic inflammation in severe asthma (154) and IL-21is increased in human asthmatic airways (155). In the early stage of asthma, the concentrations of IL-6 and IL-21 are likely insufficient to induce Th17 differentiation. This inadequacy may explain the failure to reduce airway inflammation through TGF-β inhibition at this stage. Moreover, at this stage TGF-β suppresses the activity of the immune system with the result of reducing the inflammatory symptoms of asthma, observed in animal models of asthma.

It should be added that two studies demonstrate an opposite picture. Alcorn et al. (156) report that anti-TGF-β antibodies applied prior to each QVA challenge following a period of OVA sensitization, induced airway hypersensitivity with no significant effect on airway inflammation in a mouse model. Similarly, McMillan et al. (157) have shown that anti-TGF-beta antibodies administered therapeutically, with dosing starting after the onset of established eosinophilic airway inflammation in mice, significantly reduced peribronchiolar extracellular matrix deposition, airway smooth muscle cell proliferation, and mucus production in the lung without affecting established airway inflammation and Th2 cytokine production. The contrasting results between different studies may be related to varying levels of TGF-β in each asthma model. As Zhou et al. (31) have shown, in mice, TGF-β orchestrates Th17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-β synergizes with IL-6 and IL-21 to promote IL-23R expression, favoring Th17 cell differentiation. This effect increases with TGF-β level and reaches an apex at a specific TGF-β level. TGF-β concentrations higher than this apex point repress IL-23R expression and favor Foxp3+ Treg cells. It should be remembered that at the same time, TGF-β suppresses Th2 (and Th1) cells (46) and inhibits mast cells activation (158), both involved in airway inflammation.

It is noted that a protective effect of TGF-β in early stage and a detrimental effect in late state on disease development is also typical to cancer (39, 159).

Overall, inhibiting TGF-β/Smad signaling seems to provide short-term benefits for patients with neutrophilic asthma, considering the established state of the disease. The question of potential serious adverse events associated with such treatment remains. However, the causative relationship between TGF-β/Smad signaling and long-term comorbidities is still unclear.

The TGF-β superfamily member activin-A serves various biological functions and shares signaling pathways with TGF-β1. Ex vivo stimulations of nasal tissue from patients with nasal polyps have suggested a direct induction of each other’s expression at the mRNA level by activin-A and TGF-β1 (160). Additionally, recent findings indicate that Activin-A induces apoptosis of human lung adenocarcinoma A549 cells through the endoplasmic reticulum stress pathway (161). If this mechanism extends to other cancer types, it could elucidate the negative correlation between AR and the risk of these cancers. In contrast to the two mechanisms proposed earlier, this mechanism also predicts a beneficial effect of AR on cancer prognosis.

It is suggested here, that irrespective of the specific disease, allergy patients should individually be classified into two distinct groups: patients with high level of circulating TGF-β and Th17 cytokines and those with levels lower than or close to normal levels. The author hypothesizes that allergy patients belonging to the first group will display cell metabolism biased toward glycolysis. They will be more prone to develop obesity, insulin resistance, hypertension and DM2. These patients will also be subject to a higher risk of cancer compared with normal subjects. Patients belonging to the second group will display OXPHOS-biased cell metabolism, a lower association with metabolic dysregulations, and a reduced risk of cancer compared with normal subjects. Subjects belonging to the first group should be more closely watched for metabolic syndrome and cancer.

It is notable that asthma and AR often coexist. Estimates suggest that 19-38% of patients with AR also have concurrent asthma (162), while 85–95% of patients with asthma also experience AR (163). Drawing from the earlier discussions, the author posits that, in most cases, AR will tend to coexist more frequently with eosinophilic asthma and less so with neutrophilic asthma.

The distinct inflammatory pathways of AR and neutrophilic asthma likely contribute to their contrasting associations with metabolic dysregulations and cancer risk. Given that TGF-β, IL-1β and IL-6 are essential for Th17 cell differentiation, the connection between neutrophilic asthma (characterized by high levels of these cytokines) and metabolic dysregulation and the risk of cancer becomes apparent. Specifically, in neutrophilic asthma, levels of IL-1β surpass those observed in eosinophilic asthma (notably, IL-6 levels in asthmatic patients do not correlate with the presence of neutrophils in the airways (164)). In comparison to AR, neutrophilic asthma displays higher values of both TGF-β and IL-1β circulating levels. The difference in cytokine levels between these two allergic conditions accounts for the opposing associations of neutrophilic asthma and allergic rhinitis with most types of cancer and metabolic dysregulations.

It is noteworthy that the involvement of TGF-β in metabolic dysregulations has been previously documented (165). Nevertheless, to the author’s knowledge, this is the first piece of work that establishes a connection between TGF-β/Smad pathway, IL-1β and IL-6 levels, metabolic pathways, the type of allergy, metabolic dysregulations, and the risk of cancer within a unified framework.

The schematic relationship between TGF-β levels, TGF-β signaling, metabolic pathways, metabolic dysregulations, allergic rhinitis and cancer risk, is depicted in Figure 1 .