Response of Cellular Innate Immunity to Cnidarian Pore-Forming Toxins

Abstract

A group of stable, water-soluble and membrane-bound proteins constitute the pore forming toxins (PFTs) in cnidarians. They interact with membranes to physically alter the membrane structure and permeability, resulting in the formation of pores. These lesions on the plasma membrane causes an imbalance of cellular ionic gradients, resulting in swelling of the cell and eventually its rupture. Of all cnidarian PFTs, actinoporins are by far the best studied subgroup with established knowledge of their molecular structure and their mode of pore-forming action. However, the current view of necrotic action by actinoporins may not be the only mechanism that induces cell death since there is increasing evidence showing that pore-forming toxins can induce either necrosis or apoptosis in a cell-type, receptor and dose-dependent manner. In this review, we focus on the response of the cellular immune system to the cnidarian pore-forming toxins and the signaling pathways that might be involved in these cellular responses. Since PFTs represent potential candidates for targeted toxin therapy for the treatment of numerous cancers, we also address the challenge to overcoming the immunogenicity of these toxins when used as therapeutics.

Keywords: actinoporin; cnidarian pore forming toxins; inflammation; innate immune response; potassium efflux.

Figure 1

Host cellular responses to the low and high concentrations of cnidarian PFTs. Pore formation of cnidarian PFTs may lead to difference cellular responses in host cells. At high doses of PFTs, multiple pores in the cell membrane cause an imbalance between intra- and extracellular osmotic pressures, resulting in sudden cell burst. Lower doses of PFTs can induce the intrinsic defense mechanism—autophagy that promotes intracellular engulfment and degradation. If the damage to the cell membrane cannot be repaired, the cell may undergo either programmed cell death (apoptosis) or NLRP3-dependent programmed necrosis, through p38 MAPK or NLRP3 inflammasome pathway, respectively. These two signaling pathways are also involved in either the cell survival with the restoration of intracellular osmotic environment or the activation of the cellular innate immune response, releasing pro-inflammatory proteins. In certain circumstances, inflammation is followed immediately by apoptosis or necrosis.