Induction of IL-17A Precedes Development of Airway Hyperresponsiveness during Diet-Induced Obesity and Correlates with Complement Factor D

Abstract

Obesity is a risk factor for the development of asthma. Obese mice exhibit innate airway hyperresponsiveness (AHR), a characteristic feature of asthma, and IL-17A is required for development of AHR in obese mice. The purpose of this study was to examine the temporal association between the onset of AHR and changes in IL-17A during the development of obesity by high-fat feeding in mice. At weaning, C57BL/6J mice were placed either on mouse chow or on a high-fat diet (HFD) and examined 9, 12, 15, 18, or 24 weeks later. Airway responsiveness to aerosolized methacholine (assessed via the forced oscillation technique) was greater in mice fed HFD versus chow for 24 weeks but not at earlier time points. Bronchoalveolar lavage and serum IL-17A were not affected by either the type or duration of diet, but increased pulmonary IL17a mRNA abundance was observed in HFD versus chow fed mice after both 18 and 24 weeks. Flow cytometry also confirmed an increase in IL-17A+ γδ T cells and IL-17A+ CD4+ T (Th17) cells in lungs of HFD versus chow fed mice. Pulmonary expression of Cfd (complement factor D, adipsin), a gene whose expression can be reduced by IL-17A, decreased after both 18 and 24 weeks in HFD versus chow fed mice. Furthermore, pulmonary Cfd mRNA abundance correlated with elevations in pulmonary Il17a mRNA expression and with AHR. Serum levels of TNFα, MIP-1α, and MIP-1β, and classical markers of systemic inflammation of obesity were significantly greater in HFD than chow fed mice after 24 weeks, but not earlier. In conclusion, our data indicate that pulmonary rather than systemic IL-17A is important for obesity-related AHR and suggest that changes in pulmonary Cfd expression contribute to these effects of IL-17A. Further, the observation that increases in Il17a preceded the development of AHR by several weeks suggests that IL-17A interacts with other factors to promote AHR. The observation that the onset of the systemic inflammation of obesity coincided temporally with the development of AHR suggest that systemic inflammation may be one of these factors.

Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α

“…Serum TNF-␣ is elevated in obesity (22,36,45,58), including in Cpe fat vs. WT mice (58), and TNF-␣ can induce many of the other serum cytokines and chemokines that are also elevated in the serum in obesity (2,15,30,33,41,47,58). Our data indicate increases in serum concentrations of many cytokines and chemokines in Cpe fat vs. WT mice (Fig.…”

“…The chronic, low-grade, systemic inflammation that characterizes obesity promotes other obesity-related conditions (18,23,42,54) and may also play a role in the etiology of obesity-related asthma (26,49,53). Circulating TNF-␣ is increased both in obese humans and obese mice (22,36,45,58) and may be of relevance for asthma, since exogenous administration of TNF-␣ has the capacity to induce AHR (55). TNF-␣ also has the capacity to induce many of the other cytokines and chemokines whose circulating concentrations are elevated in obesity, including MCP-1, G-CSF, IL-9, IP-10, IL-17A, and KC (2,15,30,33,41,47,58).…”

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

“…However, airway reactivity in obese mice is increased in mice deficient in tumor necrosis factor receptor 1 (21); therefore, global strategies to block tumor necrosis factor signaling are unlikely to be effective in this form of obese asthma (22). Another mediator that has been associated with the development of this inherent airway reactivity of obesity is IL-17A: increased IL-17A 1 gd T cells and TH17 cells have been found in the lungs of mice rendered obese through a high-fat diet (23). Inherent airway reactivity in response to high-fat diet-induced obesity also appears to involve increased M1 macrophages with NLRP3 activation, IL-1b production, and innate lymphoid cells in the lung (24).…”

A Common Pathway to Obesity and Allergic Asthma

“…In the 1980s, it became clear that susceptibility to cigarette smoking, and hence COPD risk, was indeed conferred by preexisting airway hyperresponsiveness and eosinophilia, partially vindicating Orie, at least on the importance of these host characteristics in conferring increased risk for COPD, independent of cigarette smoking (2)(3)(4)(5)(6). This work also…”

“…Although about one-third of the U.S. population is obese, many recent studies of asthmatic populations report a prevalence of obesity of 50% or more in these individuals (1). Studies investigating the pathogenesis of asthma in obesity using animal models suggest that obesity causes an asthma-like phenotype through innate, non-Th2 pathways (2,3). Indeed, there appears to be a phenotype of asthma, more common in women, with late-onset disease and low levels of markers of allergic inflammation (4).…”