bims-inflin 2024-12-29 papers

Commun Biol. 2024 Dec 25. 7(1): 1694

PKM2-mediated STAT3 phosphorylation promotes acute liver failure via regulating NLRP3-dependent pyroptosis.

Songman Yu, Siya Pei, Min Zhang, Shang Gao, Jun Chen, Lihua Duan, En Hu, Yang Wang, Yan Huang.

Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by high-grade inflammation and multi-organ failure. Our previous study shows that targeting the M2 isoform of pyruvate kinase (PKM2) to inhibit macrophage inflammation may be a promising strategy for ALF treatment. however, the mechanism by which PKM2 regulates the inflammatory response is unclear. Here we demonstrate that PKM2 contributes to ALF by modulating NLRP3-mediated pyroptosis activation in liver macrophages. The specific knockout of PKM2 in myeloid cells reduces mortality and alleviates hepatic injury in D-galactosamine/LPS-induced ALF mice. Single-cell transcriptome analysis suggests that NLRP3 inflammasome activation of macrophages involves in ALF, knockout of PKM2 in macrophages reduces the expression of NLRP3, and activation of pyroptosis. Pharmacological inhibition of the PKM2 nuclear translocation, but not glycolytic activity, protects mice from ALF. Pharmacological and genetic inhibition of PKM2 attenuates NLRP3-mediated pyroptosis activation and consequently reduces the release of IL-1β and IL-18 by macrophages. Mechanistically, PKM2 translocates into the nucleus and combines with STAT3, enhancing its phosphorylation and recruitment to the NLRP3 promoter region, thereby increasing NLRP3 expression. This work defines PKM2 acts as an important nonmetabolic regulator of NLRP3 that modulates pyroptosis activation in macrophages and guides future therapeutic strategies development for ALF.

DOI: https://doi.org/10.1038/s42003-024-07227-w

Elife. 2024 Dec 24. pii: RP101248. [Epub ahead of print]13

Gasdermin D-mediated neutrophil pyroptosis drives inflammation in psoriasis.

Jian Liu, YuYing Jiang, ZiYue Diao, DanDan Chen, RuiYuan Xia, BingWei Wang, Shuo Yang, ZhiQiang Yin.

Psoriasis is a multifactorial immune-mediated inflammatory disease. Its pathogenesis involves abnormal accumulation of neutrophils and T-cell-related abnormalities. Pyroptosis is a type of regulated cell death associated with innate immunity, but its role in psoriasis is unclear. In this study, we found that gasdermin D (GSDMD) is higher in human psoriatic skin than that in normal skin, and in imiquimod-induced psoriasis-like mouse skin, the expression of Gsdmd was most significantly altered in neutrophils and Il1b was also mainly expressed in neutrophils. Immunohistochemical staining of serial sections of skin lesions from psoriasis patients and healthy control also showed that GSDMD expression is higher in psoriasis lesion, especially in neutrophils. Gsdmd deficiency mitigates psoriasis-like inflammation in mice. GSDMD in neutrophils contributes to psoriasis-like inflammation, while Gsdmd depletion in neutrophils attenuates the development of skin inflammation in psoriasis and reduces the release of the inflammatory cytokines. We found that neutrophil pyroptosis is involved in and contributes to psoriasis inflammation, which provides new insights into the treatment of psoriasis by targeting neutrophil pyroptosis.

Keywords: gasdermin D; human; immunology; inflammation; mouse; neutrophil; psoriasis; pyroptosis; treatment

DOI: https://doi.org/10.7554/eLife.101248

mSystems. 2024 Dec 26. e0110624

Exploiting gasdermin-mediated pyroptosis for enhanced antimicrobial activity of phage endolysin against Pseudomonas aeruginosa.

Dorota Kuc-Ciepluch, Karol Ciepluch, Daria Augustyniak, Grzegorz Guła, Barbara Maciejewska, Artur Kowalik, Ewelina Jop, Zuzanna Drulis-Kawa, Michał Arabski.

Pyroptosis is an inflammatory immune response of eukaryotic cells to bacterial lipopolysaccharide (LPS) and other pathological stimuli, leading to the activation of the gasdermin D (GSDMD) and secretion of pore-forming domain GSDMDNterm, facilitating the release of cytokines. Additionally, GSDMDNterm exhibits antibacterial properties through interactions with bacterial outer membranes (OM). We explored alternative antimicrobial strategy to determine whether inducing natural pyroptosis via GSDMD activation by P. aeruginosa LPS could enhance the effectiveness of recombinant phage endopeptidase KP27 (peptidoglycan-degrading enzyme) against P. aeruginosa, enabling penetration through OM and bacterial killing synergistically. Our findings demonstrated that recombinant GSDMD alone exhibited antibacterial effects against wild-type P. aeruginosa with smooth LPS, while recombinant GSDMDNterm efficiently permeabilized both smooth LPS-bearing and O-chain-deficient P. aeruginosa potentially synergizing with endolysin KP27. Transcriptomic analyses revealed the activation of the immune system pathways in response to LPS, mainly in monocytic cells, in contrast to epithelial A549 or HeLa cell lines. LPS-induced pyroptosis in monocytes led to GSDMD cleavage and the release of interleukins, regardless of the nature/origin of the LPS used. However, the pyroptosis stimulation by LPS in the antibacterial assay was not effective enough for bacterial OM permeabilization and enhancement of endolysin activity. We assume that leveraging pyroptosis induction in monocytic cells to augment the bactericidal activity of endolysins may be limited.
IMPORTANCE: Recombinant GSDMDNterm protein was able to efficiently permeabilize P. aeruginosa outer membranes and increase endolysin activity against bacteria, producing either long LPS O-chains or lack them entirely. The obtained results suggest the limited possibility of using the natural process of pyroptosis occurring in monocytic cells to enhance the bactericidal effect of recombinant phage endolysins against Gram-negative bacteria infection.

Keywords: Pseudomonas aeruginosa LPS; endolysin; gasdermin D; outer membrane permeabilization; pyroptosis

DOI: https://doi.org/10.1128/msystems.01106-24

Cell Mol Life Sci. 2024 Dec 27. 82(1): 21

Exogenous acetate attenuates inflammatory responses through HIF-1α-dependent glycolysis regulation in macrophage.

Na Li, Yi Gong, Yalin Zhu, Bo Li, Changli Wang, Zhefan Wang, Jun Wang, Jie Huang, Jinjun Bian, Yan Zhang.

Cytokine storm is a hallmark for acute systemic inflammatory disease like sepsis. Intrinsic microbiome-derived short-chain fatty acid (SCFAs) like acetate modulates immune cell function and metabolism has been well studied. However, it remains poorly investigated about the effects and the underlying mechanism of exogenous acetate in acute inflammation like sepsis. Here, we observed that serum acetate accumulates in patients undergoing abdominal gastrointestinal surgery and in septic mice. Short exposure to high-dose exogenous acetate protects mice from sepsis by inhibiting glycolysis in macrophages, both in vivo and in vitro. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) stabilization or overexpression reverses the decreased glycolysis and pro-inflammatory cytokine production in macrophages and abrogates acetate's protective effect in septic mice. Meanwhile, we also found acetyl-CoA synthetase-2, but not GPR41 or GPR43, plays a key role in acetate's immunosuppressive effect. Acetate transiently increases acetyl-coenzyme A production, promoting histone acetylation and decreasing acetyl-transfer to NF-κB p65. These findings suggest that short exposure to mM-level acetate inhibits macrophage immune response linked to HIF-1α-dependent glycolysis. Taken together, we demonstrate short-term exposure of exogenous acetate could regulate inflammatory responses through attenuating HIF-1α-dependent glycolysis.

Keywords: Acetate; Glycolysis; HIF-1alpha; Inflammation; Macrophage

DOI: https://doi.org/10.1007/s00018-024-05521-8