Poly-gamma-glutamic acid from Bacillus subtilis upregulates pro-inflammatory cytokines while inhibiting NLRP3, NLRC4 and AIM2 inflammasome activation

Abstract

Poly-gamma-glutamic acid (γ-PGA) is a natural, edible and non-toxic polymer synthesized by Bacillus subtilis and is suggested as a safe biomaterial for the use in hydrogels and vaccine adjuvants. However, the effect of γ-PGA on inflammasome activation has not yet been studied in macrophages. Inflammasomes, which are intracellular multi-protein complexes, promote acute and chronic inflammation via interleukin-1β or interleukin-18 maturation, and they are known targets for metabolic syndromes and cancer. In this study, we observed that γ-PGA attenuated NLRP3, NLRC4 and AIM2 inflammasome activation, whereas it upregulated pro-inflammatory cytokine expression in human and murine macrophages. Although γ-PGA had conflicting effects on cytokine production and maturation, it clearly alleviated the severity of lipopolysaccharide-induced endotoxin shock in an animal model. Thus, we suggest γ-PGA as a candidate to control inflammasome-mediated disorders.

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

“…In addition, we could not exclude the possibility of other inflammasomes45 or their related pathways46 also involved in the mouse IgAN model at least because the treatment with shNLRP3 could not entirely prevent or improve the IgAN mice. This proposition should be warranted for further investigation.…”

Carnosol inhibits inflammasome activation by directly targeting HSP90 to treat inflammasome-mediated diseases

“…Previous studies have shown that the inflammasome components become secreted out of the cell together upon inflammasome activation [61][62][63] , on the other hand, recent studies show that the levels of inflammasome components like ASC, caspase-1, and NLRP3 remain unchanged in the cell lysate 24,[64][65][66] . The contradiction may be due to the difference in the cell type, stimuli and the stimulation time or strength.…”

Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity

“…NLRP3 inflammasome is a multiple protein complex composed of innate immune sensor NLRP3, ASC, and caspase-1 14 – 17 . The assembly of this complex results in the activation of caspase-1, which promotes the cleavage of pro-IL-1β and pro-IL-18 to produce mature and functional IL-1β and IL-18 18 , 19 , so it plays a central role in innate immunity and inflammation.…”