Innate Immunity: Orchestrating Inflammation and Resolution of Otitis Media

Abstract

Otitis media (OM) is a common disease in young children, accounting for more office visits and surgeries than any other pediatric condition. It is associated with an estimated cost of five billion dollars annually in the USA. Moreover, chronic and recurrent middle ear (ME) disease leads to hearing loss during critical periods of language acquisition and learning leading to delays in reaching developmental milestones and risking permanent damage to the ME and inner ear in severe cases. Therefore, research to understand the disease pathogenesis and identify new therapeutics is important. Although OM is a multifactorial disease, targeting the molecular mechanisms that drive inflammation and OM resolution is critical. In this review, we discuss the current evidence suggesting that innate immune receptors and effectors play key roles in OM by mediating both the ME inflammatory responses and recovery.

Keywords: IL-1ß; Inflammasome; Inflammation; Innate immunity; Middle ear; TLR.

Fig. 1

Different innate immune signaling sensors implicated in OM. Toll-like receptors (TLRs) are membrane proteins that signal through either a MyD88-dependent inflammatory cytokine response and/or a TRIF (Tir-domain-containing adaptor inducing interferon β)-dependent type-1 interferon response (IRF). The NOD-like receptors (NLRs) organize into the large complexes known as inflammasomes which activate and release IL (interleukin)-1β and IL-18. Other members of the NLR family (NOD1 and NOD2) upon recognition of bacterial peptidoglycans self oligomerize into large structures and recruit the scaffold protein RIP2 (receptor interacting protein 2) which mediates a TAK1 (TGFβ activated kinase) activation of MAP kinase (MAPK), p38, JNK (c-Jun N-terminal kinase), and NFκB (nuclear factor κB) among other transcription factors. DNA sensors represent another class of innate immune receptors that can recognize bacterial and viral nucleic acid particles triggering an inflammatory response. These innate immune sensors regulate which transcription factors are activated, that in turn modulate the expression of pro-inflammatory and anti-inflammatory genes that regulate the host inflammatory response and healing