NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

Abstract

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1β secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1β blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1β. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere’s disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

Genetic Hearing Loss Associated With Autoinflammation

“…Caspase-1 can process pro-IL-1β to mature IL-1β, which is secreted. Reproduced from Figure S1, Nakanishi et al (6).…”

Programmed Necrosis and Disease:We interrupt your regular programming to bring you necroinflammation

“…Overactivation of pyroptosis by pathogens can lead to widespread cell death, acute organ failure, sepsis, and septic shock [113]. Furthermore, patients carrying a gain-offunction mutation in inflammasome genes (NLRP1, NLRP3, and NLRC4) present with a wide spectrum of multi-organ inflammatory symptoms due to spontaneously increased inflammasome activation and IL-1β production [114][115][116]. Finally, inflammasome and caspase 1 activation have been implicated in myriad chronic inflammatory or autoimmune diseases, including atherosclerosis [117], MS [118,119], diabetes [120], obesity [121], AD [122], and Parkinson's disease [123], suggesting that either pharmacological or genetic inhibition of inflammasomes could significantly alleviate symptoms and reduce disease severity in experimental animals [117][118][119][120][121][122][123] or in patients [124].…”

Growth factor and receptor malfunctions associated with human genetic deafness

“…A rare example of a lipid messenger is sphingosine‐1‐phosphate (S1P) or lysosphingolipid, a sphingolipid that binds to its S1PR2 receptor in the inner ear, which is necessary for hearing in human and mouse . In addition to the classic signaling molecules involved in hearing mentioned above, NLRP3 is part of the inflammosome complex and variants cause over‐production of the cytokine interleukin (IL)‐1β result in hearing loss …”

“…15 In addition to the classic signaling molecules involved in hearing mentioned above, NLRP3 is part of the inflammosome complex and variants cause over-production of the cytokine interleukin (IL)-1β 16 result in hearing loss. 17 Juxtacrine signals mediated by NOTCH pathways establish the sensory epithelium, including hair cells and supporting cells. 18 In humans, WNT 19 and BMP 20 family members are required for development of the auditory system.…”