Regulation of Inflammation-Related Myeloid Cell Death By Polycomb Repressive Complex 1.1
Authors: Fukuta Takanori , Nakajima-Takagi Yaeko , Koide Shuhei , Oshima Motohiko , Iwama Atsushi 
Published: December 2024

Programmed cell death is a fundamental biological phenomenon encompassing various forms, such as apoptosis, pyroptosis, necroptosis, and ferroptosis. Its role is increasingly recognized in the development and progression of numerous diseases, including infectious diseases, autoimmune disorders, and cancers. For example, inflammasome activation and the subsequent pyroptosis, one form of inflammatory cell death, have been implicated in the progression of myelodysplastic syndrome (Sallman DA and List A, Blood 133:1039-1048, 2019).

Polycomb repressive complex 1 (PRC1) is an epigenetic regulator that represses transcription through monoubiquitination of histone H2A at lysine 119. Canonical PRC1 maintains hematopoietic stem cell function and regulates differentiation of hematopoietic stem and progenitor cells. PRC1.1, composed of PCGF1, BCOR, KDM2B, RING1B, and RYBP/YAF2, is one of the non-canonical PRC1 and loss-of-function mutations in BCOR have been identified in 4.2% of myelodysplastic syndrome (Damm, et al. Blood 122:3169-3177, 2013). We recently showed that PRC1.1 is a negative regulator of myeloid differentiation and serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis (Nakajima-Takagi, et al. elife 12:e83004, 2023). However, the role of PRC1.1 in the regulation of inflammation and inflammatory cell death remains elusive.

To address this question, we generated hematopoietic cell-specific Pcgf1 or Bcor conditional knockout mice by transplanting bone marrow (BM) cells from Rosa26Cre-ERT; Pcgf1fl/fl or Rosa26Cre-ERT; Bcorfl/Y mice into wild-type mice followed by tamoxifen treatment of the recipient mice (referred to as Pcgf1Δ/Δand BcorΔ/Δ mice, respectively). Administration of lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria and a Toll-like receptor 4 (TLR4) ligand, induced massive cell death of hematopoietic cells in the BM of Pcgf1Δ/Δmice. Enhanced cell death was also observed when extracellular membrane vesicles from Escherichia coli were administered. LPS-induced cell death of BM hematopoietic cells was also observed in BcorΔ/Δ mice, suggesting that PRC1.1 negatively regulates hematopoietic cell death induced by infection with Gram-negative bacteria.

Morphological analysis of BM specimens revealed predominant destruction of myeloid cells such as neutrophils and monocytes, with flow cytometric analysis confirming enhanced cell death in the myeloid cell fractions. Interestingly, cell death was not induced by the TLR2/TLR1 ligand Pam3CSK4 or the TLR3 ligand poly(I:C). LPS-induced cell death was completely rescued in double KO mice for Pcgf1 and Tlr4, indicating that the TLR4 signaling pathway mediates LPS-induced cell death. Moreover, administration of tumor necrosis factor alpha (TNF-α) also induced massive cell death of BM myeloid cells in Pcgf1-deficient mice in a manner similar to LPS. Treatment of Pcgf1-deficient myeloid cells by either LPS or TNF-α also induced moderate but significant cell death in vitro, which was suppressed by the addition of zVAD-fmk, a pan-caspase inhibitor, indicating that PRC1.1 plays an important role in the negative regulation of caspase-dependent cell death induced by LPS and TNF-α.

Taken together, our findings reveal that PRC1.1 is a new negative regulator of inflammation-related cell death of myeloid cells. We are currently engaged in the identification of the responsible caspase-dependent cell death pathway and the epigenetic regulation of myeloid cell death by PRC1.1.