Trends in NLRP3 inflammasome research in ischemic stroke from 2011 to 2022: A bibliometric analysis

Abstract Background Ischemic stroke is a leading cause of permanent disability and death globally. The nucleotide‐biding oligomaerization domain (NOD)‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome is a multi‐protein complex that plays a role in ischemic stroke. Recently, research on the role of NLRP3 in ischemic stroke has developed rapidly worldwide. However, there is no bibliometric analysis of NLRP3 in ischemic stroke to date. Aim Through bibliometric analysis, the aim of this study was to assess the current state of research on NLRP3 in the field of ischemic stroke research worldwide over the past 12 years and to identify important results, major research areas, and emerging trends. Methods Publications related to NLRP3 in ischemic stroke from January 1, 2011 to December 31, 2022 were obtained from the Web of Science Core Collection (WoSCC). We used HistCite, VOSviewer, CiteSpace, and Bibliometrix for bibliometric analysis and visualization. The Total Global Citation Score (TGCS) was employed to assess the impact of publications. Results We found that research of NLRP3 in ischemic stroke developed rapidly starting in 2011. 601 relevant studies have been published in 245 journals over the past 12 years. Journal of Neuroinflammation and International Immunopharmacology were the most productive journals and Journal of Neuroinflammation was the most cited journal. Additionally, Stroke and Journal of Cerebral Blood Flow & Metabolism were the most co‐cited journal. The most productive country was China (records = 430) and the most productive university was the Zhejiang University (records = 24). Arumugam TV (TGCS = 949) was the most cited author in this field. NLRP3 inflammasome activation, nf–κb, oxidative stress, and inflammation were the knowledge bases for the research in this field. Conclusion This study is a scientometric study utilizing quantitative and qualitative methods to comprehensively review the publications on NLRP3 in ischemic stroke. This information provides a reference for scholars to further study NLRP3 in ischemic stroke.


| INTRODUC TI ON
Stroke remains the leading cause of death and long-term disability worldwide, with ischemic stroke accounting for approximately 85% of all cases. 1,2 Ischemic stroke is a disease induced by cerebral blood flow cessation. The treatment of ischemic stroke is based on the restoration of blood flow in the ischemic area. 3 Thrombolytic treatment is the treatment of choice for acute ischemic stroke. Many patients with ischemic stroke, however, are not eligible for this treatment because of the narrow time window for treatment and the risk of cerebral hemorrhage. 4 In addition, the process of reconstitution of blood flow can lead to further damage of ischemic tissue through infiltration of neutrophils, disturbance of cellular ion homeostasis, accumulation of ROS, and a subsequent inflammatory response leading to cell death. 5 Although significant advancement has been made in the last few decades in neuroprotective therapies and the salvage of dead neurons, and rehabilitation methods have been developed to address poststroke deficits; no significant progress has been made in the treatment and clinical recovery of stroke. 6 Occlusion of a major vessel such as the internal carotid artery (ICA) or the middle cerebral artery (MCA) leads to an immediate cessation of oxygen and glucose supply and rapid progression to infarction in the MCA region unless recanalization is achieved in time. Hypoxic cells of the ischemic parenchyma, mainly neurons, respond by upregulating and secreting danger signals, called damage-associated molecular patterns (DAMPs); which themselves trigger secondary signaling cascades. Postischemic aseptic inflammation has both protective and deleterious effects on disease progression. Overall, the molecular mechanisms of postischemic neuronal inflammatory injury are complex and yet to be fully investigated. 7 In recent years, researchers have recognized a new inflammasome signaling pathway, NLRP3 inflammasome containing receptor 3, as a potentially important mediator for detecting cellular injury and mediating post-stroke inflammation. [8][9][10] NOD-like receptors (NLRs) are pathogen-recognition receptors expressed mainly in the cytoplasm that can detect signals from intracellular invaders. 11 There are different categories of NLRs that form the inflammasome; including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, NLRC5, and AIM2. 12 Among these inflammasomes, NLRP3 is the most characteristic, encoded by the cold-induced autoinflammatory syndrome-1 (CIAS-1) gene, and highly expressed in neuronal cells and immune cells. 13,14 The NLRP3 inflammasome is also the most widely investigated and is thought to be closely associated with aseptic inflammation that is mainly located in the cytoplasm. 15,16 The NLRP3 protein, the adapter protein ASC, and the inflammatory caspase-1 are three sections in the NLRP3 inflammasome. 17 Multiple mechanisms regulate NLRP3 inflammatory vesicles after ischemic stroke. 18 ROS production after ischemic stroke can trigger neuronal cell damage, brain edema, and neurological deficits by stimulating the brain inflammatory response and NLRP3 inflammasome. 5,19 Suppression of the NLRP3 inflammasome pathway is thought to exert neuroprotective effects in ischemic stroke models. Research in the role of NLRP3 in ischemic stroke is active and promising, therefore an analysis of the hot spots and trends within the field is warranted.
Bibliometrics is a convenient and fast new method for qualitative research and quantitative analysis of publications. 20 It focuses on the metrological features of literature, and identifies different characteristics such as countries, institutions, journals, authors, and keywords for various publications in a given field over a period of time 21 ; enabling researchers to summarize the current status and developmental trends of a research field or a specific disease, and provide direction and ideas for future research. 22 Scientometric analysis generally consists of three steps: (1) obtaining literature from accessible databases; (2) analyzing it through software tools, and (3) writing the manuscript.
With this method, researchers can quickly dig deeper into the evolution of topics, major research areas, and new research directions in a particular research area. 23 Bibliometrics as a complementary research method that has been widely used in many disciplines. 24 However, bibliometric studies of NLRP3 in ischemic stroke are still lacking.
In this study, we analyzed publications on NLRP3 in ischemic stroke using a bibliometric approach and systematically evaluated the status of recent NLRP3 research in ischemic stroke injury, current research priorities, and new research trends for systematic evaluation; highlighting landmark results and pointing out future research directions.

| ME THODS
There are no animal studies, no human studies, no potentially identifiable human images, or data presented in this manuscript; therefore, ethical approval is not required in this work.

| Data source and search strategy
The Web of Science Core Collection (WoSCC) was employed to obtain studies related to NLRP3 in ischemic stroke from January 1, 2011 to December 31, 2022. To obtain studies on NLRP3-related ischemic stroke in the past 12 years, we used the following search strategy: TOPIC: ("NLRP3") AND (TOPIC ("ischemic stroke" OR "cerebral ischemia" OR "ischaemic stroke" OR "brain ischemia" OR "cerebral ischaemia" OR "cerebral infarction" OR "brain ischaemia" OR "brain infarction")). 25 The language in our search is restricted to English. The type of literature is limited to articles and reviews.
All the eligible data were downloaded from the WoSCC and further analyzed by scientometric tools.

K E Y W O R D S
bibliometric analysis, ischemic stroke, NLRP3, visualization analysis, web of science

| Statistical analysis
HistCite Pro 2.1 26 was used to calculate the records, total local citation score (TLCS), and total global citation score (TGCS) of each publication, journal, country, productive institution, and author.
We used VOSviewer (1.6.13) to identify highly productive countries/regions, institutions, journals and authors, as well as major co-cited journals, authors and references; and to construct relevant visualization networks. 27 The link between nodes indicated the cooccurrence relationship, and the size of the link indicated the cooccurrence frequency of two nodes. We used CiteSpace V software to explore the trends and dynamics of scientific research in research related to NLRP3 in ischemic stroke, as well as visualize and analyze knowledge domains and emerging trends 20 ; including network of authors, countries, institutions, co-cited authors and references, and dual-map overlay of citations. 23,28 Cluster analysis timeline views of clusters were performed on the keywords, and the clusters were named according to the extracted keywords. In addition, we identified keywords with strong citation bursts by CiteSpace V. R package "bibliometrix" and Rstudio software (version 2022.12.0 + 353) were employed to explore the word cloud of keywords, collaboration worldmaps, core journals based on Bradford's law (Bradford's law can be used to describe the dispersion of citations in a topic or field and to identify the most cited journals in a field or discipline 29 ), F I G U R E 1 Annual output of research related to NLRP3 in ischemic stroke (A) and country/region scientific production world map of NLRP3 research in ischemic stroke (B). three-field plots, annual scientific production worldmaps, and cocited journals with most TGCS. Another web tool (https://bibli ometr ic.com/app) was used for analyzing the cooperation between different countries.

| Annual publications analysis
A total of 601 publications associated with NLRP3 in ischemic stroke were retrieved from WoSCC, 453 articles, and 141 reviews (Table S1). Starting from 2011, the number of papers published in this field increased from 2 to 143, with rapid growth in the number of papers published annually ( Figures 1A, S1, Table S2

| Leading countries
Among the 601 publications we obtained, the corresponding authors were distributed in 37 countries or regions, as illustrated in Figure 1B. On the world map, a country or region in blue means that there were corresponding authors from there, and the intensity of the blue color was proportional to the number of publications in that country or region; the darker the blue color, the more publications were published. China, the United States, and Germany had the largest number of publications, accounting for 71.55%, 17.80%, and 4.33%, respectively. In addition to these three countries, there were some other countries with more than 10 publications; including South Korea, UK, Australia, Iran, Italy, Japan, and Canada. The top 5 countries in terms of number of articles published were China, USA, Germany, South Korea, and UK (Table 1). Additionally, the top 10 most cited countries were China, USA, Germany, Australia, Singapore, South Korea, UK, Canada, Japan, and Italy (Table 1). Figure 2A shows a map of national or regional collaboration on NLRP3 in the field of ischemic stroke. If there was some kind of collaboration between two countries or regions, they would be connected by a red line, the thickness of which is proportional to the number of collaborations. As shown in Figure 2A, mainland China and the United States were the central countries of the publications. There were collaborations between various countries. In particular, the collaboration between the United States and mainland China has 43 co-published papers (Table S3). Additionally, through using the CiteSpace software and an online bibliometric app, the similar results of collaboration between different countries were presented in Figure 2B,C.

| Core journals and co-cited journals
The literature related to NLRP3 in ischemic stroke was published in 245 journals. The 10 journals with the highest productivity are TA B L E 1 Top 10 productive countries and most cited countries.

Most productive countries
Most cited countries shown in Table 3.   Table 4). The co-authorship network is presented in Figure 6A. Figure 6B shows the results for the top 20 authors with the highest number of published papers.

| Active authors and co-cited authors
One of the most relevant authors was Wang J, who published 16 articles related to NLRP3 in the field of ischemic stroke. The red line in Figure 6B

| Publications and co-cited reference analysis
We performed a statistical analysis of 601 publications and found that 34 documents had more than 100 citations. The top 10 most cited publications were shown in Table 5.

| Co-occurrence of keywords and cluster analysis
A total of 1584 keywords were identified, and 108 keywords appeared more than 10 times. Word cloud can visually illustrate the keywords and highlight the keywords with high frequency of occurrence. To quickly visualize the most prominent keywords in NLRP3-related studies in the field of ischemic stroke, word cloud was generated for the extracted keywords. Figure 8A showed the word cloud of the keywords. The font size of a word represented its frequency of occurrence. The most frequent keyword was NLRP3 inflammasome, followed by activation, stroke, oxidative stress, and nfκb ( Figure 8B). Among the 1584 keywords analyzed TA B L E 2 Top 10 most productive and cited institutions. in relation to studies on the topic of NLRP3 and ischemic stroke, a total of 222 keywords were identified as having appeared more than 5 times and the co-occurrence between these 240 keywords was visualized ( Figure 8C). The top 19 keywords with strongest citation bursts were shown in Figure S3. The results indicated that receptor antagonist, caspase 1, and il1 beta were the top three keywords with the strongest citation bursts. After naming the clusters with the terms extracted from the included publications, we found 11 clusters. The 11 clusters were named "#0 nlrp3 inflammasome-mediated neuronal death", "#1 acupuncture", "#2 -induced interleukin-1 secretion", "#3 absence", "#4 natural compound", "#5 adenosine-dependent activation", "#6 telmisartan", "#7 tissue injury", "#8 il-1 production", "#9 acute stroke", and "#10 emerging role" ( Figure 8D). Additionally, the timeline view of clusters was showed in Figure S4.

| DISCUSS ION
This study is the first bibliometric study on NLRP3 in ischemic stroke research worldwide. The aim of this study was to perform a bibliometric analysis of research trends and hotspots in NLRP3 in ischemic stroke using the WoSCC database, HistCite Pro 2.1, VOSviewer, R package "bibliometrix", and Citespace. We searched for 601 articles

F I G U R E 5
The dual-map overlay of journals associated with NLRP3 research in ischemic stroke. His latest research in the field of ischemic stroke shows that delayed treatment with fluoxetine or atomoxetine plus limited voluntary running promotes motor recovery in mice after ischemic stroke. 40

| CON CLUS ION
With the help of HistCite, bibliometrix, CiteSpace, and VOSviewer; structure and timing of the field. This study also summarizes some specific mechanisms by which NLRP3 affects neuronal survival in ischemic stroke.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
The original contributions presented in the study are included in the article/supplementary material, and further inquiries are available by contacting the corresponding/first authors.