Intervertebral disc degeneration (IVDD), a prevalent degenerative disorder with substantial socioeconomic impacts, is closely linked to endplate inflammation and chronic low back pain. Its pathogenesis involves multifactorial mechanisms, including long-term chronic mechanical loading, external trauma, and hereditary factors. Emerging evidence highlights Propionibacterium acnes (P. acnes), a gram-positive bacterium with potent proinflammatory properties, as a key contributor to IVDD progression. This review systematically analyses the latest literature on related studies, focusing on the molecular mechanisms of IVDD induced by P. acnes. Three molecules play an important role in the induction of IVDD by P. acnes, namely, IL-1β, MIF, and MMP. In addition, P. acnes induces IVDD through three core mechanisms, namely, proinflammatory (activation of TLR2, production of large amounts of ROS to promote inflammation), pyroptosis (production of large amounts of NLRP3 through the TXNIP-NLRP3 axis and the ROS-NLRP3 axis), and apoptosis (promotion of Bax and inhibition of Bcl-2 expression through the TLR2-JNK pathway). The dissection of these related important molecules and pathogenic mechanisms can lead to a better understanding of the role of P. acnes in IVDD. It can provide an important theoretical basis for future research. However, the current study's lack of large-scale clinical validation, unresolved colonization controversies, and limited experimental methods are limitations. Therefore, in the future, it is still necessary to improve the relevant theories and resolve the current controversies through more advanced experimental methods and higher quality clinical studies. In conclusion, the study of P. acnes-induced IVDD is promising, and further research can be conducted in the future, which is expected to develop novel therapeutic approaches for P. acnes, thus effectively slowing down the development of IVDD.

01 Nov 2024·International Immunopharmacology

MIF aggravates experimental autoimmune prostatitis through activation of the NLRP3 inflammasome via the PI3K/AKT pathway

Article

Author: Feng, Rui ; Zhang, Fei ; Zhang, Song ; Liang, Chaozhao ; Meng, Tong ; Zhang, Meng ; Jin, Chen ; Meng, Jialin

In our investigation, we investigated the role of macrophage migration inhibitory factor (MIF), a key cytokine, in chronic nonbacterial prostatitis (CNP), an underexplored pathology. Elevated MIF expression was observed in the serum of individuals with chronic prostatitis-like symptoms (CP-LS) as well as in serum and tissue samples from experimental autoimmune prostatitis (EAP) mouse model. Treatment with ISO-1, a specific MIF antagonist, effectively mitigated prostatic inflammation and macrophage infiltration, thereby emphasizing the critical role of MIF in orchestrating immune responses within the prostate microenvironment. Further analyses revealed that MIF stimulates the PI3K/AKT and NLRP3 inflammasome pathways, which are integral to inflammation and cellular immunity. Pharmacological inhibition of the PI3K/AKT pathway by LY294002 substantially reduced prostatic inflammation and macrophage infiltration, potentially by inhibiting NLRP3 inflammasome activation. These findings collectively suggest that MIF is a potential diagnostic marker for CNP and suggest that targeting MIF or its downstream signalling pathways, PI3K/AKT and NLRP3, might represent a novel therapeutic strategy for this condition.

31 Dec 2023·Hematology

Polymorphisms of inflammation-related genes and susceptibility to childhood leukemia: evidence from a meta-analysis of 16 published studies

Review

Author: Tang, Xiufu ; Liu, Cui ; Zeng, Qiuping ; Ren, Haoyan ; Xie, Yongwu ; Liu, Ting

OBJECTIVEThis study was to comprehensively clarify the associations between single nucleotide polymorphisms (SNPs) in inflammatory genes and the susceptibility to childhood leukemia.METHODSEligible articles were collected from the databases of PubMed, EMBASE, Cochrane Library, CNKI and Wan Fang. The pooled odds ratios (ORs) and 95% conﬁdence intervals (95% CIs) were calculated to estimate the association strength by using the STATA 15.0 software.RESULTSSixteen studies were enrolled. These studies mainly evaluated SNPs in 13 genes, including C-X-C motif chemokine ligand 12 (CXCL12), toll-like receptor (TLR)-4, TLR6, TLR9, CD14, interleukin (IL)-1β, NLR family pyrin domain containing 3, IL-4, interleukin 4 receptor, IL-10, IL-13, macrophage migration inhibitory factor (MIF) and tumor necrosis factor-α. The meta-analysis indicated that CXCL12 rs1801157 (AG vs GG: OR = 1.99; 95%CI = 1.20-3.30; p = 0.008; AA + AG vs GG: OR = 1.92; 95%CI = 1.18-3.12; p = 0.009), TLR6 rs5743810 (TC vs TT: OR = 0.58; 95%CI = 0.39-0.85; p = 0.005), IL-10 rs1800871 (TC vs CC: OR = 1.19; 95%CI = 1.01-1.41; p = 0.044), rs1800872 (AC vs AA: OR = 1.53; 95%CI = 1.22-1.92; p < 0.001) and MIF rs755622 (CG versus GG: OR = 1.33; 95%CI = 1.07-1.67; p = 0.012) polymorphisms were associated with the risk of childhood leukemia. No significant correlations were found between SNPs in other genes and the childhood leukemia risk. Subgroup analyses of rs1800871 and rs1800872 confirmed the conclusions obtained in their overall meta-analytical processes.CONCLUSIONCXCL12 rs1801157, TLR6 rs5743810, IL-10 rs1800871, rs1800872 and MIF rs755622 polymorphisms may represent candidate biomarkers for the risk prediction of childhood leukemia.

News (Medical) associated with MIF x NLRP3

18 Jul 2022

·www.prnewswire.com

Apaxen appoints Graham K. Dixon as Chairman and prepares for clinical testing of its lead inflammasome inhibitor

Completion of IND enabling studies with lead compound MFC-1040 by late 2022 Target for series B round financing by early 2023 to fund clinical development GOSSELIES, Belgium, July 18, 2022 /PRNewswire/ -- Apaxen S.A., a privately-held biotechnology company, developing novel next generation NLRP3 inflammasome inhibitor drugs for treatment of chronic inflammatory and auto-immune diseases, announced today that it has appointed Graham K. Dixon, PhD as Chairman of its Board of Directors and that it is preparing for clinical testing of its lead product MFC-1040. The appointment of Dr Graham Dixon as Chairman is an important step in the transformation of Apaxen from a pre-clinical to a clinical stage company. During his successful carreer in C-suite management positions at companies such as Galapagos, Addex Therapeutics and Mithra Pharmaceutical, he was instrumental to the regulatory approval of three pharmaceutical products, twelve proof of concept studies and ten clinical stage licensing deals. He is an experienced non-executive director and board chairman as well as an advisor to several venture capital organisations and their portfolio companies. In addition, Apaxen expects to complete IND enabling pre-clinical testing of its lead NLRP3 inflammasome inhibitor MFC-1040 by end of 2022 and aims to raise series B round financing by early 2023 to fund the clinical development plans of the company. Bart Wuurman, CEO of Apaxen, stated: "We are very pleased to welcome Graham as Chairman of Apaxen's Board of Directors with his experience and extensive track record of leading biotechnology companies through strategic periods of growth. He will be a great asset for the company entering its phase of clinical development and we look forward to working with him." Graham Dixon, newly appointed Chairman of Apaxen, comments: "I am very excited to join the Apaxen team. With its novel approach to inhibiting NLRP3 inflammasomes, the Company is moving into the next stage of growth and we will be looking for new high quality investors to support the company financially. I look forward to guiding Apaxen during this exciting time in the Company's development and supporting the team to achieve our mission of helping patients with severe inflammatory and autoimmune diseases." About Apaxen Founded in 2018, Apaxen raised €5.4 million since its A round funding in 2019 from a syndicate of VC investors and with the support of the Walloon region to develop a pipeline of NLRP3 inflammasome inhibitors with a novel mechanism of action, for treatment of chronic inflammatory and autoimmune diseases. Apaxen's clinical candidate MFC-1040 is an orally bioavailable and selective small molecule NLRP3 inflammasome inhibitor, which has demonstrated efficacy in multiple animal models of chronic inflammatory disease () and pulmonary fibrosis (). MFC-1040 acts by blocking the interaction between intracellular Macrophage Migration Inhibitory Factor (MIF) and NLRP3 to inhibit formation of NLRP3 inflammasomes (), key drivers of innate immunity and implicated in many inflammatory and auto-immune diseases. The novel Mode of Action of MFC-1040 has potential benefits for patients over other NLRP3 inflammasome inhibitors in clinical development. The Apaxen team combines the experience required for clinical development of its products and is supported by a world-class team of scientific advisors. Contacts Apaxen Bart Wuurman, CEO T: +31 64 66 23 735 E: [email protected] 48, Rue Auguste Piccard, B-6041, Gosselies, Belgium LifeSpring Life Sciences Communication, Amsterdam, the Netherlands Leon Melens T: +31 6 538 16 427 E: [email protected] Logo: SOURCE Apaxen

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