Microglial Mayhem NLRP3 Inflammasome's Role in Multiple Sclerosis Pathology

Abstract

Introduction: This review delves into the intricate relationship between NLR inflammasomes, particularly the NLRP3 inflammasome, and the immune-mediated neurodegenerative disease, multiple sclerosis (MS). While the precise etiology of MS remains elusive, compelling research underscores the pivotal role of the immune response in disease progression. Notably, recent investigations highlight the significant involvement of NLRP3 inflammasomes in various autoimmune diseases, prompting an in-depth exploration of their impact on MS.

Method: The review focuses on elucidating the activation mechanism of NLRP3 inflammasomes within microglia/macrophages (MG/MФ), examining how this activation promotes an inflammatory response that exacerbates neuronal damage in MS. A comprehensive analysis of existing literature and research findings forms the basis for understanding the intricate interplay between NLRP3 inflammasomes and MS pathogenesis.

Results: Synthesizing current research, the review provides insight into the pivotal role played by NLR inflammasomes, specifically NLRP3, in MS. Emphasis is placed on the inflammatory response orchestrated by activated MG/MФ, elucidating the cascade that perpetuates neuronal damage in the disease.

Conclusions: This review concludes by consolidating key findings and offering a nuanced perspective on the role of NLRP3 inflammasomes in MS pathogenesis. The detailed exploration of the activation process within MG/MФ provides a foundation for understanding the disease's underlying mechanisms. Furthermore, the review sets the stage for potential therapeutic strategies targeting NLRP3 inflammasomes in the pursuit of MS treatment.

Keywords: NLRP3; experimental autoimmune encephalomyelitis; inflammasome; macrophages; microglia; multiple sclerosis.

FIGURE 1

Genetic, environmental, and lifestyle factors influencing the onset of MS (created with BioRender). MS is the result of an autoimmune response caused by the dynamic interaction between genetic (A), environmental, and lifestyle factors (B).

FIGURE 2

Trends in publication, affiliated countries, and hot topic frequency analysis of related literature. (A) In 2022, the number of publications peaked at 16 articles, and the fastest growth rate was observed in 2020, reaching 400%, indicating that research in this field is rapidly developing and in a phase of rapid growth. The x‐axis represents the year, and the y‐axis represents the number of publications, sourced from the PubMed database. (B) From January 2013 to October 2023, the top 24 countries worldwide in terms of publications in this research field are shown. China ranked first with 29 articles (36.71%), followed by the United States (21 articles, 26.58%), Canada (9 articles, 11.39%), and Italy (18 articles, 9.57%). The color scale on the right (1–29) represents the number of publications; larger circles in the figure indicate more publications, sourced from the CiteSpace data analysis platform. (C) Hot topic frequency analysis of the literature. The top five most frequently occurring keywords are MG, inflammasome, NLRP3 inflammasome, neuroinflammation, and NLRP3, sourced from the CiteSpace data analysis platform.

FIGURE 3

Ranking and changes in popularity of keywords over different time periods (sourced from CiteSpace Data Analysis Platform). Initially (2013–2015), the focus was on NLRP3 inflammation, gradually followed by keywords related to inflammasomes, neuroinflammation, and other inflammation‐related studies.

FIGURE 4

Analysis of literature affiliation by gene (sourced from BioBERT Biomedical Language Representation Model). The x‐axis represents the number of publications. The BioBERT biomedical language representation model was used to mine and statistically analyze gene entities in the abstracts of these 79 articles. The gene with the highest number of publications is Nlrp3 (46 articles), followed by Casp1 (33 articles), and AGTAVPRL ranked third (30 articles).

FIGURE 5

Involvement of NLRs in the regulation of autoimmune diseases (created with BioRender). Abnormal activation of NLR inflammasomes is one of the mechanisms underlying various autoimmune diseases, including inflammatory bowel disease, rheumatoid arthritis, MS, systemic lupus erythematosus, psoriasis, and type 1 diabetes.

FIGURE 6

Activation mechanisms of NLRP3 inflammasomes [12] (created with BioRender). NLRP3 activation includes both classical and non‐classical pathways. Classical activation pathway: The priming stage of NLRP3 is initiated by binding to PAMPs or DAMPs, activating membrane‐bound TLRs, typically TLR4. The activation signal transduces into the cell, stimulating nuclear factor (NF)‐κB, which induces the expression of NLRP3, pro‐IL‐1β, pro‐IL‐18, and pro‐caspase‐1, representing the first signal. The second signal arises from changes in the intracellular environment, such as potassium efflux, lysosomal rupture, or the production of ROS. These changes can directly or indirectly activate NLRP3. Non‐classical activation pathway: Mediated by caspase‐11 in rodents and its human homologs caspase‐4/5. This means that in mice, Caspase‐11, and in humans, caspase‐4/5, can directly sense cytosolic lipopolysaccharide (LPS), leading to pore formation in the plasma membrane, activating GSDMD, inducing pyroptosis, and causing K⁺ efflux.

FIGURE 7

Roles of different immune cells in the pathogenesis of MS [55] (created with BioRender).

FIGURE 8

Anatomy and origins of MG and CNS MФ [74] (created with BioRender). EMP, erythromyeloid progenitor cells; HSC, hematopoietic stem cells; MM, meningeal macrophages; PVM, perivascular macrophages.

FIGURE 9

Mechanisms of neurodegeneration mediated by MG and MФ in progressive MS [77] (created with BioRender).

FIGURE 10

Inhibitors of the NLRP3 inflammasome activation pathway for the treatment of MS (created with BioRender).