Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. In this process, immune cells recognize foreign danger signals within themselves, release pro-inflammatory cytokines, swell, burst, and die. The released cytokines attract other immune cells to fight the infection and contribute to inflammation in the tissue. Pyroptosis promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and enhancing the host's defensive responses. However, in pathogenic chronic diseases, the inflammatory response does not eradicate the primary stimulus, as would normally occur in most cases of infection or injury, and thus a chronic form of inflammation ensues that ultimately contributes to tissue damage. Some examples of pyroptosis include Salmonella-infected macrophages and abortively HIV-infected T helper cells.

Pyroptosis is considered a critical factor in the recovery of neurological function following traumatic brain injury. Brain injury activates a molecular signaling cascade associated with pyroptosis and inflammation, including NLRP3, inflammatory cytokines, caspase-1, gasdermin D (GSDMD), and other pyroptosis-related proteins. In this study, we explored the neuroprotective effects of LDC7559, a GSDMD inhibitor. Briefly, LDC7559, siRNA-GSDMD (si-GSDMD), or equal solvent was administrated to mice with a lipopolysaccharide + nigericin (LPS + Nig) model in vitro or with controlled cortical impact brain injury. The findings revealed that inflammation and pyroptosis levels were decreased by LDC7559 or si-GSDMD treatment both in vitro and in vivo. Immunofluorescence staining, brain water content, hematoxylin, and eosin staining, and behavioral investigations suggested that LDC7559 or si-GSDMD inhibited microglial proliferation, ameliorated cerebral edema, reduced brain tissue loss, and promoted brain function recovery. Taken together, LDC7559 may inhibit pyroptosis and reduce inflammation by inhibiting GSDMD, thereby promoting the recovery of neurological function 1).

Previous studies reported that melanocortin-4 receptor (MC4R) activation exerted neuroprotection in several neurological diseases. The purpose of this study was to investigate the role of MC4R activation with RO27-3225 in suppressing neuronal pyroptosis after experimental intracerebral hemorrhage (ICH) and the underlying mechanism.

EXPERIMENTAL APPROACH: One hundred and sixty-nine (169) male CD1 mice were used. ICH was induced by right side basal ganglia injection of bacterial collagenase. RO27-3225, a selective agonist of MC4R, was injected intraperitoneally at 1 h after ICH. To elucidate the underlying mechanism, we administered the specific MC4R antagonist HS024 and the specific apoptosis signaling-regulating kinase 1 (ASK1) inhibitor NQDI-1. Neurological tests, Western blot, Fluoro-Jade C (FJC), TUNEL and immunofluorescence staining were conducted.

KEY RESULTS: The expressions of MC4R and NOD-like receptor family, pyrin domain containing 1 (NLRP1) inflammasome were increased after ICH. RO27-3225 treatment decreased neuronal pyroptosis and neurobehavioral deficits at 24 and 72 h after ICH. RO27-3225 reduced the expressions of p-ASK1, p-c-Jun N-terminal kinase (JNK), p-p38 mitogen-activated protein kinase (p38 MAPK), NLRP1 inflammasome, cleaved caspase-1 and IL-1β after ICH. HS024 pretreatment prevented the effects of RO27-3225. Similar to RO27-3225, NQDI-1 alone improved neurological functions and downregulated ASK1/JNK/p38MAPK expressions after ICH.

CONCLUSIONS AND IMPLICATIONS: RO27-3225 suppressed NLRP1-dependent neuronal pyroptosis and improved neurological functions possibly medicated by MC4R activation and inhibition of ASK1/JNK/p38 MAPK signaling pathways after experimental ICH in mice. MC4R may be a promising therapeutic target for ICH management 2).

The function of pyroptosis-related genes (PRGs) in gliomas was investigated based on the Chinese Glioma Genome Atlas (CGGA), the Cancer Genome Atlas (TCGA) and the Repository of Molecular Brain Neoplasia Data (Rembrandt) databases. In this study, using the non-negative matrix factorization (NMF) clustering method, 26 PRGs from the RNA sequencing data were divided into two subgroups. The LASSO and Cox regression was used to develop a 4-gene (BAX, Caspase-4, Caspase-8, PLCG1) risk signature, and all glioma patients in the CGGA, TCGA and Rembrandt cohorts were divided into low- and high-risk groups. The results demonstrate that the gene risk signature related to clinical features can be used as an independent prognostic indicator in glioma patients. Moreover, the high-risk subtype had rich immune infiltration and high expression of immune checkpoint genes in the tumor immune microenvironment (TIME). The analysis of the Submap algorithm shows that patients in the high-risk group could benefit more from anti-PD1 treatment. The risk characteristics associated with pyroptosis proposed in this study play an essential role in TIME and can potentially predict the prognosis and immunotherapeutic response of glioma patients 3).

Yu E, Zhang E, Lv X, Yan L, Lin Z, Siaw-Debrah F, Zhang Y, Yang S, Ruan L, Zhuge Q, Ni H. LDC7559 Exerts Neuroprotective Effects by Inhibiting GSDMD-dependent Pyroptosis of Microglia in Mice with Traumatic Brain Injury. J Neurotrauma. 2022 Aug 3. doi: 10.1089/neu.2021.0318. Epub ahead of print. PMID: 35920115.
Chen S, Zuo Y, Huang L, Sherchan P, Zhang J, Yu Z, Peng J, Zhang J, Zhao L, Doycheva D, Liu F, Zhang JH, Xia Y, Tang J. RO27-3225 attenuates NLRP1-dependent neuronal pyroptosis via MC4R/ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral hemorrhage. Br J Pharmacol. 2019 Feb 27. doi: 10.1111/bph.14639. [Epub ahead of print] PubMed PMID: 30811584.
He G, Chen Z, Zhuo S, Tang J, Hao W, Yang K, Yang C. Pyroptosis: a novel signature to predict prognosis and immunotherapy response in gliomas. Hum Cell. 2022 Sep 21. doi: 10.1007/s13577-022-00791-5. Epub ahead of print. PMID: 36129672.
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