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. 2013 Mar;182(3):819-27.
doi: 10.1016/j.ajpath.2012.11.005. Epub 2012 Dec 17.

A novel function of MUC18: amplification of lung inflammation during bacterial infection

Qun Wu  1 , Stephanie R Case, Maisha N Minor, Di Jiang, Richard J Martin, Russell P Bowler, Jieru Wang, John Hartney, Anis Karimpour-Fard, Hong Wei Chu
Affiliations

A novel function of MUC18: amplification of lung inflammation during bacterial infection

Qun Wu et al. Am J Pathol. 2013 Mar.

Abstract

Bacterial infection plays a critical role in exacerbations of various lung diseases, including chronic pulmonary obstructive disease (COPD) and asthma. Excessive lung inflammation is a prominent feature in disease exacerbations, but the underlying mechanisms remain poorly understood. Cell surface glycoprotein MUC18 (alias CD146 or melanoma cell adhesion molecule) has been shown to promote metastasis in several tumors, including melanoma. We explored the function of MUC18 in lung inflammatory responses to bacteria (eg, Mycoplasma pneumoniae) involved in lung disease exacerbations. MUC18 expression was increased in alveolar macrophages from lungs of COPD and asthma patients, compared with normal healthy human subjects. Mouse alveolar macrophages also express MUC18. After M. pneumoniae lung infection, Muc18(-/-) mice exhibited lower levels of the lung proinflammatory cytokines KC and TNF-α and less neutrophil recruitment than Muc18(+/+) mice. Alveolar macrophages from Muc18(-/-) mice produced less KC than those from Muc18(+/+) mice. In Muc18(-/-) mouse alveolar macrophages, adenovirus-mediated MUC18 gene transfer increased KC production. MUC18 amplified proinflammatory responses in alveolar macrophages, in part through enhancing the activation of nuclear factor-κB (NF-κB). Our results demonstrate, for the first time, that MUC18 exerts a proinflammatory function during lung bacterial infection. Up-regulated MUC18 expression in lungs (eg, in alveolar macrophages) of COPD and asthma patients may contribute to excessive inflammation during disease exacerbations.

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Figures

Figure 1
Figure 1
MUC18 expression by human alveolar macrophages. A: MUC18 mRNA expression in isolated alveolar macrophages from healthy subjects (n = 4) and from patients with COPD (n = 4) or asthma (n = 4). Compared with healthy subjects, the COPD and asthma patients exhibited higher levels of MUC18 mRNA expression in alveolar macrophages. B: Representative MUC18 protein immunostaining in human lung tissues. In contrast to alveolar macrophages (arrows) in healthy lung, the alveolar macrophages in COPD and asthma patients had increased MUC18 protein (purple) expression. Data are expressed as means ± SEM. Original magnification, ×400. AM, alveolar macrophage; BV, blood vessel.
Figure 2
Figure 2
MUC18 expression by mouse alveolar macrophages. A: Alveolar macrophages of WT mice (Muc18+/+), but not Muc18 knockout mice (Muc18−/−), stain positive for MUC18 (arrows). B: Double immunofluorescent staining of MUC18 (green) and F4/80 (red) demonstrates MUC18 localization to alveolar macrophages from Muc18+/+ mice (arrows). C: Western blot shows MUC18 protein in alveolar macrophages of Muc18+/+, but not Muc18−/− mice. Original magnification, ×400.
Figure 3
Figure 3
Proinflammatory cytokines and neutrophils in mouse lungs. Muc18+/+ and Muc18−/− mice were intranasally inoculated with saline solution (control) or with Mp at 1 × 108 CFU per mouse. After 4 hours of infection, KC levels in BAL fluid (A) and lung tissue (B) were significantly lower in Muc18−/− mice than in Muc18+/+ mice. Moreover, levels of neutrophils (C) and TNF-α (D) in BAL fluid of Muc18−/− mice were lower than in Muc18+/+ mice. Data are expressed as means ± SEM. n = 5 to 8 mice per group. *P < 0.05.
Figure 4
Figure 4
Mp load in lung tissue and BAL. Muc18+/+ and Muc18−/− mice were intranasally inoculated with Mp at 1 × 108 CFU per mouse. After 4 hours (A) and 24 hours (B) of infection, Mp levels were quantified in entire left lungs and in BAL. Data are expressed as means ± SEM. n = 5 to 8 mice per group.
Figure 5
Figure 5
Reduced KC production in ex vivo Muc18−/− alveolar macrophages. Alveolar macrophages were isolated from Muc18+/+ and Muc18−/− mice that were intranasally infected with Mp at 1 × 108 CFU per mouse for 4 or 24 hours. Cells were incubated for 24 hours without further stimulation. Data are expressed as means ± SEM. n = 3 replicates. *P < 0.05.
Figure 6
Figure 6
Reduced KC production in in vitro Muc18−/− alveolar macrophages. Alveolar macrophages from Mp-naïve Muc18+/+ and Muc18−/− mice were isolated and treated with medium (−), Mp (MOI = 1), or Pam2CSK4 (Pam2; 10 ng/mL) for 24 hours. Data are expressed as means ± SEM. n = 4 replicates. *P < 0.05.
Figure 7
Figure 7
Adenovirus-mediated MUC18 gene transfer in Muc18−/− mouse alveolar macrophages resulted in MUC18 protein expression (A) and in amplified KC production after stimulation for 24 hours with the TLR2 agonist Pam2CSK4 (10 ng/mL) (B). Data are expressed as means ± SEM. n = 3 replicates. *P < 0.05. AdControl, control adenovirus; AdMUC18, adenovirus-expressing mouse MUC18.
Figure 8
Figure 8
Role of NF-κB in MUC18-mediated KC production in mouse alveolar macrophages. A: Muc18−/− alveolar macrophages exhibit less nuclear NF-κB p65 activation than Muc18+/+ alveolar macrophages after 30 minutes of stimulation with the TLR2 agonist Pam2CSK4 (10 ng/mL). B: KC induction (4 hours) in Pam2CSK4-stimulated Muc18−/− alveolar macrophages with adenovirus-mediated MUC18 gene transfer is inhibited by the selective NF-κB inhibitor helenalin. Data are expressed as means ± SEM. n = 3 replicates. *P < 0.05. DMSO, dimethyl sulfoxide; OD, optical density.
Figure 9
Figure 9
Proinflammatory cytokine KC in mouse BAL fluid. Muc18+/+ and Muc18−/− mice were intranasally inoculated with saline solution (control) or nontypeable Haemophilus influenzae (NTHi) at 1 × 107 CFU per mouse. After 4 hours of infection, BAL fluid was collected for ELISA measurement of KC levels. Data are expressed as means ± SEM. n = 3 or 4 mice per group. *P < 0.05.
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