Mucociliary Defense: Emerging Cellular, Molecular, and Animal Models

Abstract

Respiratory tissues are bombarded by billions of particles daily. If allowed to accumulate, these particles can cause injury, inflammation, or infection, and thus may significantly disrupt airflow and gas exchange. Mucociliary defense, a primary mechanism for protecting host tissues, operates through the coordinated functions of mucus and cilia that trap and eliminate inhaled materials. Mucociliary function is also required for the elimination of endogenous cells and debris. Although defense is necessarily robust, it is also tightly regulated to minimize physiologic disruption of the host. Indeed, mucociliary dysfunction contributes to the pathogenesis of many lung diseases-including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and cystic fibrosis-in which airflow limitation, inflammation, persistent tissue injury, and structural remodeling occur. Here, we highlight recent advances in cilia and mucin biology, the importance of well-controlled mucociliary interactions, and the need to better understand how these regulate innate barrier and immune defense.

Keywords: airway epithelium; goblet cell; mucin; mucus.

Figure 1.

Mucociliary differentiation. During airway epithelial differentiation, multiciliated cell (MCC) and secretory cell fates are determined by Notch signaling, such that signal-sending cells assume the multiciliated fate and cells receptive of Notch signaling become secretory cells. Downstream of the Notch signaling event, nascent MCCs launch an MCC-specific gene expression program under the control of the EDM (EDF4/5, DP1, MCIDAS [multiciliate differentiation and DNA synthesis associated cell cycle protein]) transcriptional complex and several secondary transcription factors, including forkhead box J1 (FOXJ1) (inset). This turns on the expression of hundreds of structural and regulatory ciliary genes, and initiates the motile ciliogenesis pathway, which leads to the assembly of 200–300 cilia per MCC. Mature MCCs contain motile cilia decorated with membrane-tethered mucins. Secretory cells synthesize secretoglobins and mucins, and their transcriptional development program is reviewed by Whitsett (pp. S143–S148) (59).

Figure 2.

Assembly and secretion of polymeric mucins. Two polymeric mucin genes, MUC5AC and MUC5B, are expressed by airway surface and glandular epithelia. Translation occurs in the endoplasmic reticulum, where CTCK (C-terminal cysteine knot) regions of MUC5AC and MUC5B form interchain homodimers. Dimers are transported to the Golgi apparatus, where they are O-glycosylated with GalNac (yellow squares), followed by Core 1-4 glycosylation with Gal (yellow circles) and GlcNac glycans (blue squares). Core glycosylated mucins are then elaborated with Gal and GlcNac additions that form extensions or branches. Two specialized sugars, fucose (red triangles) and sialic acid (purple diamonds), can be added to Gal (and also to GlcNac in the case of fucose), creating biophysically and immunologically specialized glycoconjugates. Glycosylated complexes then multimerize via N-terminal disulfide assembly in the trans Golgi. Once fully synthesized, mucins are exported from the Golgi and stored in secretory vesicles for subsequent release by regulated exocytosis.