MUC1: The First Respiratory Mucin with an Anti-Inflammatory Function

Abstract

MUC1 is a membrane-bound mucin expressed on the apical surfaces of most mucosal epithelial cells. In normal lung epithelia, MUC1 is a binding site for Pseudomonas aeruginosa, an opportunistic human pathogen of great clinical importance. It has now been established that MUC1 also serves an anti-inflammatory role in the airways that is initiated late in the course of a bacterial infection and is mediated through inhibition of Toll-like receptor (TLR) signaling. MUC1 expression was initially shown to interfere with TLR5 signaling in response to P. aeruginosa flagellin, but has since been extended to other TLRs. These new findings point to an immunomodulatory role for MUC1 during P. aeruginosa lung infection, particularly during the resolution phase of inflammation. This review briefly summarizes the recent characterization of MUC1's anti-inflammatory properties in both the respiratory tract and extrapulmonary tissues.

Keywords: MUC1; Pseudomonas aeruginosa; Toll-like receptor; inflammation; lung; membrane-tethered mucin.

Figure 1

Schematic diagram of the MUC1 glycoprotein. Proceeding from the NH₂-terminus to the COOH-terminus, MUC1 consists of heavily O-glycosylated ectodomain containing a variable number of tandem repeat (VNTR) region, a SEA domain with a glycine-serine (Gly-Ser) proteolytic cleavage site, a single pass transmembrane (TM) domain, and a cytoplasmic tail (CT). The amino acid sequence of a single TR is indicated. Five potential sites for N-linked glycosylation are present in the MUC1 ectodomain and SEA domain. The sequence of the 72-amino acid MUC1-CT is illustrated with potential binding sites for various kinases and adapter proteins at tyrosine-containing (red) and serine/threonine-containing (blue) sequence motifs.

Figure 2

Hypothetical model for the proposed anti-inflammatory role of MUC1 in response to P. aeruginosa lung infection. (1) Flagellin engagement of TLR5 triggers a canonical MyD88 → IRAK1/4 → TRAF6 → TAK1 → NF-κB-signaling pathway to generate an early proinflammatory response with increased IL-8 production; (2) Inhaled P. aeruginosa activates alveolar macrophages (Mφ) to release TNF, which increases MUC1 expression by airway epithelial cells (AEC) through a TNFR → MEK1/2 → ERK1 → Sp1 pathway; (3) P. aeruginosa stimulation of AEC drives TGF-α release; (4) TGF-α binding to EGFR stimulates phosphorylation of the MUC1-CT at its tyrosine⁴⁶ residue; (5) Phosphorylated MUC1-CT binds to the intracellular domain of TLR5, thereby blocking recruitment of MyD88 to TLR5, inhibiting inflammatory signaling, and contributing to the later resolution of inflammation.