Increased susceptibility to otitis media in a Splunc1-deficient mouse model

Abstract

Otitis media (inflammation of the middle ear) is one of the most common diseases of early childhood. Susceptibility to otitis is influenced by a number of factors, including the actions of innate immune molecules secreted by the epithelia lining the nasopharynx, middle ear and Eustachian tube. The SPLUNC1 (short palate, lung, nasal epithelial clone 1) protein is a highly abundant secretory product of the mammalian nasal, oral and respiratory mucosa that is thought to play a multifunctional role in host defense. In this study we investigated Splunc1 expression in the ear of the mouse, and examined whether this protein contributes to overall host defense in the middle ear and/or Eustachian tube. We found that Splunc1 is highly expressed in both the surface epithelium and in submucosal glands in these regions in wild-type mice. In mice lacking Splunc1, we noted histologically an increased frequency of otitis media, characterized by the accumulation of leukocytes (neutrophils with scattered macrophages), proteinaceous fluid and mucus in the middle ear lumens. Furthermore, many of these mice had extensive remodeling of the middle ear wall, suggesting a chronic course of disease. From these observations, we conclude that loss of Splunc1 predisposes mice to the development of otitis media. The Splunc1−/− mouse model should help investigators to better understand both the biological role of Splunc1 as well as host defense mechanisms in the middle ear.

Proteomic Characterization of Middle Ear Fluid Confirms Neutrophil Extracellular Traps as a Predominant Innate Immune Response in Chronic Otitis Media

“…Calprotectin, a dimer of S100A8 and S100A9, has also been shown to bind to NETs and is reportedly required for NET antifungal activity[ 52 ], likely making it important in OM. SPLUNC, another abundant protein in the MEEs has been demonstrated to contribute to pulmonary host defense, and its depletion in mice leads to middle ear infection[ 53 , 54 ]. Finally, MUC5B, the predominant mucin in human COM fluid[ 14 ] has also shown to be required for airway defense, with its absence leading to severe middle ear infection in mice[ 55 ].…”

An in vitro model of murine middle ear epithelium

“…BPIFA1 was identified as a candidate for OM in a recent GWAS study (Rye et al . , 2012) and loss of the protein has been implicated in the development of OM in aged mice (Bartlett et al . , 2015).…”

Interactions between the otitis media gene, Fbxo11, and p53 in the mouse embryonic lung

“… Rye et al (2012 ) identified significant associations at several loci, including CAPN14 , GALNT14 , BPIFA3 and BPIFA1 , identifying novel candidate genes for further analysis. Interestingly, a mouse model of BPIFA1 was recently shown to demonstrate an increased susceptibility to OM ( Bartlett et al, 2015 ). In a second GWAS study ( Allen et al, 2013 ), a novel susceptibility locus on chromosome 2 was identified, with the relevant SNP lying in the intergenic region between CDCA7 and SP3 .…”