Introduction: Chronic inflammatory diseases, including
retinal diseases that are a major cause of vision loss, are associated with activation of the
nucleotide-binding domain and
leucine-rich repeat containing (NLR) protein-3 (NLRP3)
inflammasome pathway. In
chronic disease, the
inflammasome becomes self-perpetuating, indicating a common pathway in such diseases irrespective of underlying etiology, and implying a shared
solution is feasible.
Connexin43 hemichannels correlate directly with NLRP3
inflammasome complex assembly (shown here in models of
retinal disease).
Connexin43 hemichannel-mediated
ATP release is proposed to be the principal activator signal for
inflammasome complex assembly in primary signal-sensitized cells.
Connexin hemichannel block on its own is sufficient to inhibit the
inflammasome pathway. Areas covered: We introduce chronic
retinal disease, discuss available preclinical models and examine findings from these models regarding the targeting of
connexin43 hemichannels and its effects on the
inflammasome. Expert opinion: In over 25
animal disease models,
connexin hemichannel regulation has shown therapeutic benefit, and one oral
connexin hemichannel blocker,
tonabersat (Xiflam), is Phase II ready with safety evidence in over 1000 patients. Regulating the
connexin hemichannel provides a means to move quickly into clinical trials designed to ameliorate the progression of devastating
chronic diseases of the eye, but also elsewhere in the body.