GRIM19 downregulation-induced pyroptosis of macrophages through NLRP3 pathway in adenomyosis

Research question: Does the absence of GRIM19 affect pyroptosis of macrophages? Is the release of IL-1β caused by pyroptosis a relevant factor in the regulation of adenomyosis progression?

Design: Endometrial tissues were collected from patients with (n = 12) and without (n = 12) adenomyosis. GRIM19 expression of adenomyosis tissues was analysed by western blot and real-time polymerase chain reaction (RT-PCR). In GRIM19 knockdown macrophages, pyroptosis-related factors expressions were also measured by western blot and RT-PCR. The human endometrial stromal cells (HESC) were co-cultured with GRIM19-depleted macrophages and IL-1β neutralizing antibody to detect the effects of pyroptosis of macrophages on apoptosis, proliferation and migration of HESC.

Results: The expression of GRIM19 was significantly lower in adenomyosis (P = 0.0002). In THP-1-derived macrophages, the expression of NLRP3 (P < 0.0001), ASC (P = 0.0176), caspase-1 (P = 0.0368), GSDMD (P = 0.0453) and IL-1β (P = 0.0208) are increased after downregulation of GRIM19. GRIM19 knockdown induced the release of IL-1β (P = 0.0195) in THP-1-derived macrophages. The apoptosis of HESC co-cultured with GRIM19 knockdown macrophages was significantly inhibited (P < 0.0001), the proliferation (P = 0.0254) and migration (P < 0.0001) were markedly promoted. Existence of IL-1β neutralizing antibody in supernatants recovered the effects (P < 0.0001) of GRIM19 knockdown macrophages on HESC.

Conclusions: GRIM19 downregulation induces pyroptosis of macrophages through NLRP3 pathway, increases the secretion of IL-1β and promotes adenomyosis progression.