Trans-cortical vessels in the mouse temporal bulla bone are a means to recruit myeloid cells in chronic otitis media and limit peripheral leukogram changes

Abstract

Chronic otitis media, inflammation of the middle ear, is a sequel to acute otitis media in ∼8% of children. Chronic otitis media with effusion is the most common cause of childhood deafness and is characterised by effusion of white blood cells into the auditory bulla cavity. Skull flat bones have trans-cortical vessels which are responsible for the majority of blood flow in and out of the bone. In experimental models of stroke and aseptic meningitis there is preferential recruitment of myeloid cells (neutrophils and monocytes) from the marrow in skull flat bones. We report trans-cortical vessels in the mouse temporal bone connect to the bulla mucosal vasculature and potentially represent a means to recruit myeloid cells directly into the inflamed bulla. The mutant mouse strains Junbo (MecomJbo/+) and Jeff (Fbxo11Jf/+) develop chronic otitis spontaneously; MecomJbo/+ mice have highly cellular neutrophil (90%) rich bulla exudates whereas Fbxo11Jf/+ mice have low cellularity serous effusions (5% neutrophils) indicating differing demand for neutrophil recruitment. However we found peripheral leukograms of MecomJbo/+ and Fbxo11Jf/+ mice are similar to their respective wild-type littermate controls with healthy bullae and infer preferential mobilization of myeloid cells from temporal bulla bone marrow may mitigate the need for a systemic inflammatory reaction. The cytokines, chemokines and haematopoietic factors found in the inflamed bulla represent candidate signalling molecules for myeloid cell mobilization from temporal bone marrow. The density of white blood cells in the bulla cavity is positively correlated with extent of mucosal thickening in MecomJbo/+, Fbxo11Jf/+, and EdaTa mice and is accompanied by changes in epithelial populations and bone remodelling. In MecomJbo/+ mice there was a positive correlation between bulla cavity WBC numbers and total bacterial load. The degree of inflammation varies between contralateral bullae and between mutant mice of different ages suggesting inflammation may wax and wane and may be re-initiated by a new wave of bacterial infection. Clearance of white blood cells and inflammatory stimuli from the bulla cavity is impaired and this may create a pro-inflammatory feedback loop which further exacerbates otitis media and delays its resolution.

Temporal bone marrow of the rat and its connections to the inner ear

“…Middle ear-associated marrow is located in the ectotympanic bone (bulla) at sites of contact to the outer environment: two ring-shaped clusters are found around the tubal orifice and the external auditory meatus. Middle ear bone marrow has been found to provide local immune protection in otitis in mice ( 3 ) and is connected to the middle ear mucosa through bone channels. We have seen similar channels in rat, connecting ectotympanic bone marrow to the middle ear cavity.…”

“…Temporal bone marrow distribution from different animals (Figure 3) was consistent, displaying a cluster at the cochlear apex (CAEM, Figure 3A), one around semicircular canal arms, outside the otic capsule (PNEM, Figure 3B), and one around the base of the cochlea and the vestibule, extending around the crus commune (VEM, Figure 3C). Endochondral bone marrow clusters (Figure 3D), were significantly smaller than PNEM [CAEM = 0.06 ± 0.05 mm 3 (n = 21), VEM = 0.09 ± 0.13 mm 3 (n = 15), PNEM = 3.18 ± 1.26 mm 3 (n = 11)] and displayed sex-linked volume differences (Figure 3D).…”

“…In brain immunology, cranial bone marrow has recently been acknowledged as a major player, given its connections to the dura through bone channels allowing bidirectional transfer of immune cells and molecules [reviewed in ( 2 )]. Temporal bone marrow is also known to play a major local immune role in the middle ear (where it produces immune cells related to otitis responses, which can therefore occur without appreciable systemic reactions) ( 3 ) and around the endolymphatic sac (where it changes morphologically ( 4 ) and functionally ( 5 ) in response to immune challenges to the ear). In both cases, temporal bone marrow was found to directly connect to its target (middle ear mucosa and vestibular aqueduct, respectively) through bone channels.…”