Obesity and airway responsiveness: Role of TNFR2

Abstract

Obese mice exhibit innate airway hyperresponsiveness (AHR), a feature of asthma. Tumor necrosis factor alpha (TNFα) is implicated in the disease progression and chronic inflammatory status of both obesity and asthma. TNF acts via two TNF receptors, TNFR1 and TNFR2. To examine the role of TNFR2 in the AHR observed in obese mice, we generated obese Cpefat mice that were either sufficient or deficient in TNFR2 (Cpefat and Cpefat/TNFR2−/− mice, respectively) and compared them with their lean controls (WT and TNFR2−/− mice). Compared to WT mice, Cpefat mice exhibited AHR to aerosolized methacholine (measured using the forced oscillation technique) which was ablated in Cpefat/TNFR2−/− mice. Bioplex or ELISA assay indicated significant increases in serum leptin, G-CSF, IL-7, IL-17A, TNFα, and KC in obese versus lean mice, as well as significant obesity-related increases in bronchoalveolar lavage fluid (BALF) G-CSF and IP-10, regardless of TNFR2 status. Importantly, BALF IL-17A was significantly increased over lean controls in Cpefat but not Cpefat/TNFR2−/− mice. Functional annotation clustering of significantly affected genes identified from microarray analysis comparing gene expression in lungs of Cpefat and WT mice, identified blood vessel morphogenesis as the gene ontology category most affected by obesity. This category included several genes associated with AHR, including endothelin and trkB. Obesity increased pulmonary mRNA expression of endothelin and trkB in TNFR2 sufficient but not deficient mice. Our results indicate that TNFR2 signaling is required for the innate AHR that develops in obese mice, and suggest that TNFR2 may act by promoting IL-17A, endothelin, and/or trkB expression.

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

“…For example, this inherent airway reactivity is reduced in mice deficient in tumor necrosis factor receptor-2 (20). 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).…”

Obesity: Changing Asthma in the 21st Century

“…TNF-a has also been implicated in mouse studies of obesity and asthma (15). Given the therapeutic relevance of this pathway, this observation likely warrants further investigation.…”

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

“…These data suggest that exposure to this common air pollutant may be a particular problem for the obese person with asthma. Obese mice also exhibit innate AHR and have greater airway responsiveness after acute exposure to O 3 than lean mice (32,50,58,59,62).…”

“…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).…”

“…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).…”