High Interleukin (IL)-6 is Associated with Lower Lung Function and Increased Likelihood of Metabolic Dysfunction in Asthma

Asthma is a common condition characterized by chronic airway inflammation that is mediated by a wide variety of cells and cytokines. In some patients, airway inflammation is primarily driven by type 2 (T2) helper cells [1] and in others by non-T2 mechanisms [2]. A subset of patients with asthma are obese, with difficult to treat symptoms and poor response to traditional treatments [3]. Interleukin-6 (IL-6) promotes differentiation of T helper cells into pro-inflammatory subtypes, inhibits interferon (IFN)-γ signaling, and inhibits generation of regulatory T cells (Treg) [4‐7]. IL-6 has increased expression in individuals with obesity [8, 9]. Several observations also suggest that IL-6 may play a key role in asthma pathogenesis, particularly in patients with obesity [8‐12]. Lung and circulating IL-6 levels are also up-regulated in other asthma phenotypes, for example, in non-allergic asthma and patients with predominantly neutrophilic or mixed granulocytic inflammation [10‐12]. Clinically, increased IL-6 levels are associated with severe disease with more frequent exacerbations, lower lung function, and poorer asthma control [10, 13].

There is increasing prevalence of metabolic dysfunction in parallel with the increasing rates of obesity [14, 15]. Patients with obesity, asthma, and metabolic dysfunction have more severe asthma, compared to non-obese patients with asthma but without metabolic dysfunction [13]. The Black population is disproportionately affected by obesity, metabolic dysfunction, and asthma [16]. Finally, there is some suggestion of a racial impact on IL-6 levels, with the Black population having higher levels than their white counterparts [14]. In order to explore the associations between IL-6, asthma, and metabolic dysfunction, we utilized the Coronary Artery Risk Development in Young Adults (CARDIA) study database https://​www.​cardia.​dopm.​uab.​edu [17]. We devised a model to obtain a cut-off for IL-6 and compared high and low IL-6 groups.

We hypothesized that high IL-6 levels would be associated with Black race, high body mass index (BMI), and metabolic dysfunction. We also aimed to show that high IL-6 is associated with asthma severity, as assessed by lung function measures.

Using the calculated IL-6 cut-off value (4.979 pg/mL), the cohort was divided into high (305/3369) and low IL-6 groups (3064/3369) (Table 1). High IL-6 patients did not differ from low IL-6 patients in age, asthma diagnosis, or percentage of patients reporting asthma symptoms in the past year. However, the high IL-6 group was more likely to be Black (66.6% vs. 43.8%, p < 0.001), have higher BMI [median 31.85 (26.90–40.25) kg/m² vs. 27.82 (24.29–32.23) kg/m², p < 0.001], have high blood pressure (36.9% vs. 22.4%, p < 0.001), higher rates of metabolic dysfunction (31.1% vs. 18.7%, p < 0.001), higher HbA1c [5.6 (5.3–6) vs. 5.3 (5.1–5.6), p < 0.001], higher CRP (4.29 (1.42–9.59] vs. 1.02 (0.44–2.55], p < 0.001) and lower lung function as evidenced by lower FEV₁ [2.59 (2.20–3.17) vs. 2.99 (2.52–3.60), p < 0.001] and FVC [3.31 (2.75–4.10) vs. 3.83 (3.19–4.61), p < 0.001] (Table 1).

Multiple factors were significantly associated with high IL-6, in the univariable logistic models, including race, sex, metabolic dysfunction, and active asthma (Table 2). However, in the multivariable model male sex (OR 1.473; 95% CI 1.02–2.128), higher BMI (OR 1.024, 95% CI 1.002–1.04), Black race (OR 1.413, 95% CI 1.030–1.939), HbA1c (OR 1.302, 95% CI 1.043–1.625), and CRP (OR 1.148, 95% CI 1.116–1.182) were positively associated with the odds of high IL-6, while lung function (FEV₁) (OR 0.693, 95% CI 0.535–0.897), total cholesterol (OR 0.993, 95% CI 0.989–0.997), and fasting glucose (OR 0.991, 95% CI 0.984–0.999) were negatively associated with the odds of high IL-6 (Fig. 2; Table 2). Given the negative association between IL-6 and lung function and the observation that Black patients generally have a higher IL-6, we investigated the possibility of an interaction effect of IL-6 and race on FEV₁ using a multivariable regression model. The interactions were not significant.

Separate models were also analyzed (adjusted for other significant covariates) to determine the impact of obesity and asthma on IL-6 levels. These models demonstrated that being overweight or obese is significantly associated with higher log (IL-6), regardless of the presence or absence of co-morbid asthma. In the multivariable regression model of (log)IL-6, higher BMI, Black race, increased CRP, and metabolic dysfunction were positively associated with (log)IL-6, while lung function (FEV₁) and total cholesterol were negatively associated with (log)IL-6 (Supplement, Table S2). Multivariable analysis of FEV₁ (Supplement, Table S3a) and FVC (Supplement, Table 3b) revealed negative associations with Black race, female sex, CRP, IL-6, HbA1c, metabolic dysfunction, age, and current asthma, and a positive association with height. FVC was additionally negatively associated with diastolic blood pressure and FEV₁ was further negatively associated with ≥ 2 wheezing attacks (Supplement, Table 3b).

To ascertain factors associated with high IL-6 in asthma, we performed logistic regression of high IL-6 patients with asthma only (n = 305 or 9% of the cohort) (Table 3). In the univariable models, female sex, Black race, BMI, and CRP were positively associated with the odds of high IL-6 asthma, while FEV₁ was negatively associated with the odds of high IL-6 (Table 3). However, in the multivariable model, only Black race and CRP were positively correlated with the probability of high IL-6 asthma. We compared lung function between IL-6 levels (high: > 4.979 pg/ml and low: < 4.979 pg/ml) within asthma (presence or absence aka normal) and BMI (lean < 25 kg/m² or non-lean > 25 kg/m²) groups (Fig. 3). High IL-6 non-lean patients with asthma had a statistically lower lung function (both FEV₁ and FVC) compared to low IL-6 non-lean patients with asthma (p < 0.001). Even within the lean patients with asthma, having high IL-6 appeared to result in lower FEV₁; however, this difference was not statistically significant (p = 0.3582). Interestingly, we also found that, among the non-lean normal, there was a significantly lower lung function for patients with high IL-6 compared to those with low IL-6 (p < 0.001). Finally, multivariable modeling using race-specific cut-off (Black and white) was conducted for high IL-6. (Supplement, Table 4a and b). These models suggested association between the odds of high IL-6 and cRP (p < 0.00001, OR 1.103 95% CI 1.064–1.142) for the Black subpopulation and odds of high IL-6 and BMI (p < 0.0016, OR 1.057, 95% CI 1.021–1.093), cRP (p < 0.0001, OR 1.211 95% CI 1.149–1.276), and FEV1 (p < 0.001, OR 0.565, 95% CI 0.406–0.786) for the white subpopulation.

We found significant association between high IL-6 levels and markers of metabolic dysfunction-elevated HbA1c, as well as markers of inflammation, i.e., CRP. This shows the complex interplay between chronic inflammation and metabolic dysregulation in asthma pathogenesis. This also suggests that addressing both inflammatory and metabolic components may be crucial for the optimal management of asthma. Prior cross-sectional studies demonstrated possible connections between obesity, IL-6, and asthma severity [13]. Our study confirmed a positive association between IL-6 and obesity, and further showed significant associations between high IL-6 and features of metabolic syndrome like high blood pressure [18]. Remarkably, the median serum CRP was four times higher in patients with high IL-6. Chronic low-grade inflammation (related to high leptin and low adiponectin) and hormonal dysregulation are possible explanations for this finding [19‐21].

The impact of weight on the interaction between IL-6 and asthma is also an important consideration as leptin can increase IL-6 levels [22]. Both lung IL-6 and circulating IL-6 levels are up-regulated in patients with asthma [22]. These observations suggest that IL-6 may play a key role in disease pathogenesis in asthma and obesity-associated asthma (23, 24) Interestingly, established components of metabolic syndrome, like impaired glucose tolerance, increased fasting serum triglycerides, and low high-density lipoprotein levels, are also associated with increased plasma IL-6, raising speculative concerns of increased cardiovascular risk in asthma [24, 25].

IL-6 signaling promotes Th2 cells in select contexts, increases differentiation of effector T cells into pro-inflammatory Th17 subsets, promotes the differentiation of T follicular helper cells, and inhibits generation of regulatory T cells (Treg)[26‐28]. IL-6 is thought to evoke immune responses typical of both T2 and non-T2 inflammation as evidenced by increased serum eosinophilia and fraction of exhaled nitric oxide, as well as Th17-mediated neutrophilia in patients with high IL-6 and asthma [29, 30]. IL-6 trans-signaling has been shown to result in greater exacerbation rates and increased expression of genes associated with airway remodeling and obstruction [10]. Interestingly, in a subset of patients with high IL-6, significant T2 inflammation was not identified in the airway epithelium, suggesting a possible link between IL-6 trans-signaling (through sIL-6R) and non-T2 asthma [10, 31]. Neutrophils are purported to be a key component of non-T2 asthma [32] and might be an important source of sIL-6R in the lungs of patients with asthma [33, 34]. High IL-6 was strongly associated with Black race in our analysis. This positive relationship between high IL-6 and race has been previously reported [14], with a higher level of serum IL-6 levels in patients of African American descent. The higher prevalence of obesity and metabolic syndrome in Black individuals, as well as socioeconomic determinants of health, may in part account for the strong association [14, 15].

Several factors were negatively associated with lung function (FEV₁ and FVC) in our multivariate model, including Black race, CRP, HbA1c, and metabolic dysfunction. The method by which metabolic syndrome impacts lung function could be related to increases in pro-inflammatory cytokines, with contributions from elevated insulin, dyslipidemia, and leptin [35, 36]. Furthermore, studies have shown that a greater number of features of metabolic syndrome are strongly associated with decreased FVC and FEV₁ in patients with and without chronic pulmonary conditions like COPD and asthma [37]. Moreover, a recent study highlighted the importance of assessing body composition in understanding asthma severity. This study found that severe asthma is associated with higher visceral and subcutaneous fat areas, underscoring the potential role of morph-omics in predicting asthma outcomes [38].

Monoclonal antibodies (mABs) have revolutionized our ability to manage difficult to treat asthma [39]. Those mABs which target IL-6 and its receptor, like sarilumab and tocilizumab, are already used in rheumatological and inflammatory conditions with efficacy [40]. In a small study with two pediatric patients with severe, steroid-resistant asthma, IL-6 blockade with tocilizumab resulted in immunological and clinical improvement of asthma control and exacerbations [41]. Notably, both patients were found to have an IL-4 receptor alpha chain variant, R576 (IL-4Ra-R576), known to drive mixed TH2/TH17 airway inflammation [41, 42]. These observations suggest the plausibility of treating patients with high-IL-6 asthma with mABs, especially given the lack of available options targeting non-T2 asthma. In addition to anti IL-6 mABs, high IL-6 asthma with concomitant obesity and metabolic dysfunction may see further benefits with weight loss and management of metabolic diseases.

This study underscores the significant association between elevated IL-6 levels and asthma, particularly in the context of obesity and metabolic dysfunction. Our findings indicate that higher IL-6 levels correlate with more severe asthma as assessed by lung function, especially among individuals with obesity. These findings validate a need to better understand the pathologic role of IL-6 in asthma and perhaps the need to identify targeted therapies as being carried out in the PrecISE study (NCT04129931) [43]. Additionally, comprehensive asthma management should address both inflammatory and metabolic factors to improve patient outcomes. Future research should focus on the high IL-6 asthma population that is non-obese and free from metabolic dysfunction to fully understand the additional biological mechanisms at play.