The Role of the NLRP1 Inflammasome in the Pathogenesis of Vitiligo: A Literature Review

Abstract

Vitiligo is a skin disorder caused by the loss of melanocytes; the cells responsible for producing pigment. The loss of melanocytes results in the appearance of depigmented patches on the skin. The disease affects approximately 0.1%-2.0% of the global population and does not show a preference for any specific age group or gender. The loss of melanin in the affected areas occurs due to the abnormal apoptosis, or programmed cell death, of melanocytes. Vitiligo is classified as an autoimmune condition, in which the adaptive immune system becomes inappropriately activated and autoreactive immune cells, the cells responsible for protecting our body, mistakenly target and attack the body’s own melanocytes. Currently, we lack a clear understanding of why the body specifically targets melanocytes and identifies them as foreign cells, mounting an immune response against them and activating apoptosis, cell death, in the melanin producing agents. One recently identified candidate that has been implicated in the vitiligo immune response is the NLRP1 gene. NLRP1 is a crucial gene involved in the innate immune response, it codes for a protein that is associated with the regulation of inflammation. This gene plays a significant role in the assembly of the NLRP1 inflammasome, which is a multiprotein complex that activates our immune system in response to cellular damage caused by stress or infection. Research studies have revealed that there are differences in the NLRP1 expression and function in individuals affected by vitiligo, suggesting its potential involvement in the pathogenesis of the disease. This literature review used research containing information surrounding inflammasomes, Vitiligo, and NLRP1. Our findings indicate elevated NLRP1 expression in patients with vitiligo, correlating with increased inflammasome activity and melanocyte apoptosis.

Keywords: Vitiligo, NLRP1, inflammasome, pathogenesis, melanocytes, autoimmune disease

Introduction

Vitiligo is a chronic autoimmune disease marked by the loss of skin pigmentation as a result of melanin depletion. Melanocytes, the cells responsible for melanin production, progressively diminish, resulting in the partial or complete loss of skin coloration¹. It is important to acknowledge the global prevalence of this unpreventable disease. In a sample region of Denmark comprising 47,033 individuals, the prevalence of vitiligo was found to be 0.38%, with no significant differences in the distribution across five towns and between urban and rural areas². A meta-analysis of 82 population or community-based studies revealed that the combined prevalence of vitiligo was 0.2% (95% confidence interval: 0.1%–0.2%). Notably, significant disparities emerged, with higher prevalence rates documented in the African and Indian regions. These disparities were highlighted in a study in 2012, which examined a population of 442 individuals in India and found the prevalence of vitiligo was 9.98%. Furthermore, a 2005 study of 2,871 individuals in Nigeria found that the prevalence was 3.17%³. The prevalence of vitiligo in both these countries is notably higher compared to the global rates.

Individuals with a family history of vitiligo face an elevated risk of developing the condition. Kin of people with vitiligo were shown to have a 6% chance of developing the condition while the risk for the general population is 1% or lower. Additionally, there is a 23% probability that twins will both have vitiligo if one of them develops the condition⁴. Nevertheless,the fact that the probability is not 100% suggests that there are additional factors that influence the onset of vitiligo. Several environmental factors have been proposed as potential triggers for vitiligo, including sunburn and exposure to certain chemicals. These factors may increase the risk of developing the conditions in those that are genetically predisposed.

The NLRP1 inflammasome has gained warranted attention in the field of autoimmune research, recently. This multi-protein complex plays a key role in inflammatory responses and is a part of the innate immune system. In vitiligo specifically, the NLRP1 inflammasome is responsible for triggering inflammation in the body by releasing immune signaling molecules, cytokines. An extreme overexpression of NLRP1 can Currently, there is only an extremely basic understanding of the relationship between the NLRP1 inflammasome and vitiligo. Recent genetic association studies have identified gene polymorphisms that are linked to increased vulnerability to vitiligo, among other autoimmune diseases. However, there is a lack of focused research on new therapeutic options to combat vitiligo or other autoimmune conditions through the dysregulation of NLRP1. The objective of this review is to provide a comprehensive overview of the inflammatory processes in vitiligo and to encourage further research on these focused areas.

This article will examine the current state of research on vitiligo, with a specific focus on the role of the inflammasome NLRP1.

Vitiligo Pathogenesis

Vitiligo pathogenesis is grounded on the immune system’s misrecognition of melanocytes as foreign entities, leading to an orchestrated attack against these cells. This immune response is facilitated by the activation of T cells⁵. A T cell’s role in the immune system is identifying specific antigens on foreign or abnormal cells. When these T cells come into contact with such antigens, they mount an immune response. This immune response is characterized by the secretion of signaling molecules that promote inflammation called cytokines that function as messengers to control and direct immune responses⁶. When there is immune activation, pro-inflammatory cytokines are released, amplifying the immune response and encouraging the recruitment and activation of additional immune cells to the affected site.

Studies have revealed that in individuals with vitiligo, there is an overproduction of pro-inflammatory cytokines, including interferon-gamma (IFN-), tumor necrosis factor-alpha (TNF-), and notably, interleukin-2 (IL-2), and notably, interleukin-2 (IL-2)⁷. The overabundance of these molecules has a multifaceted impact, contributing to the disruption of the natural pigmentation process and the death of melanocytes through a process referred to as pyroptosis, a unique form of cell death associated with an inflammatory response.

One pro-inflammatory cytokine in particular, IL-2, is known for its essential role in stimulating the proliferation and differentiation of T cells, B cells, and natural killer cells, all of which constitute integral components of the immune system. More specifically, IL-2 acts as a growth factor for T cells, stimulating their replication and expansion in response to immune challenges. This function is crucial for mounting an effective immune response, as it ensures a rapid increase in the number of immune cells targeting the antigen. IL-2, compared to other cytokines, has a dual function rather than a sole purpose. Although IL-2 is responsible for activating T cells, it is also responsible for immune control through regulatory T cell (Treg) maintenance. Patients with dysfunctional IL-2 expression and overactive immune systems have excessive inflammation with diminishing immune regulation. While IL-2’s role in immune activation is significant, excessive production and dysfunction of this molecule contributes to inflammation and immune dysregulation. In the context of vitiligo, IL-2’s overproduction and malfunction is associated with the autoimmune attack on melanocytes.

The NLRP1 protein

Recent studies have shown that the NLRP1 gene is upregulated in patients with familial vitiligo. This gene is located at chromosome 17 at position 13.2 and codes for the protein NLRP1⁸. NLRP1 is 1,473 amino acids long and has a molecular weight of 165.9 kDa⁹. This protein consists of multiple essential domains¹⁰. It features a Pyrin domain (PYD) which is the site for protein-protein interactions, a NACHT domain crucial for the oligomerization (formation) of multi-protein complexes within the body, Leucine-Rich Repeats responsible for facilitating the protein-protein interactions and autoinhibition, and a FIIND (function to find) domain necessary for caspase activation, among others. Interestingly, NLRP1 has a unique interaction with Apoptosis-associated speck-like protein (ASC) involving the CARD (caspase-recruitment domain) domain for inflammasome assembly. The CARD domain in ASC essentially recruits and activates caspase-1 proteases which is key for inflammasome assembly. Moreover, proteins with a Leucine-Rich Repeat or NACHT domain have been shown to be involved in apoptosis or inflammation¹¹. NLRP1 is the only gene in the NLR family of genes that contains a Baculovirus Inhibitor of apoptosis protein Repeat (BIR) domain¹². BIR domains work to inhibit apoptosis by directly interacting with caspases. These different domains form a complex protein structure with unique features.

The multiple protein domains of NLRP1 are crucial to the formation of the inflammasome complex and the triggering of the inflammasome cascade. The PYD domain facilitates the recruitment of caspase-1 and the activation of cytokines like IL-1 and IL-18. This domain also interacts with other PYD-containing proteins, such as ASC. The NACHT domain is essential for oligomerization and activation as well as nucleotide binding¹³. Additionally, this domain is key in spotting and halting foreign invaders in the body. This intricate formation of the inflammasome complex allows an organism to efficiently react to danger signals and mount an immune response.

The NLRP1 Inflammasome in autoimmune conditions

NLRP1 is pivotal as an inflammasome component, driving innate immune responses and inflammation. NLRP1 acts as a scout for intracellular danger signals, it senses cellular stress, infections, or tissue damage. Upon recognition of these signals, NLRP1 undergoes oligomerization, assembling into a multiprotein complex known as the NLRP1 inflammasome. This inflammasome complex recruits adaptor proteins like ASC and facilitates the autoproteolytic cleavage of caspase-1, converting it into its active form. Caspase-1 contributes to inflammation by processing cytokines and triggering an immune response. Activated caspase-1 cleaves pro-inflammatory cytokines, including IL-1b and IL-18, into active forms, enabling their secretion and driving inflammation. Furthermore, activation of the NLRP1 inflammasome leads to pyroptosis, a form of cell death characterized by membrane rupture and the release of pro-inflammatory cellular content. The connections between NLRP1, inflammasomes, and autoimmunity are significant, as different forms of or genetic polymorphisms in NLRP1 have been linked to susceptibility to autoimmune diseases.

Unsurprisingly, NLRP1 is upregulated in vitiligo patients. Up-regulation of NLRP1 can result in heightened immune surveillance and response efficiency. The protein’s role in assembling inflammasomes facilitates the recognition of danger signals, any dysregulation of the inflammasome’s sensing mechanisms could lead to abnormal activation of the immune cascade. This overactivity ultimately leads to the immune system’s misrecognition of melanocytes as foreign entities. The hypersensitivity and elevated inflammation is at the core of vitiligo and many other autoimmune diseases.

The NLRP1 inflammasome and similar proteins in the NLR inflammasome family, such as NLRP3, have been associated with other autoimmune diseases as well. Genetic polymorphisms in the NLRP1 gene affect immune signaling pathways, leading to dysregulation of immune responses directed at thyroid tissue, contributing to the development of autoimmune thyroid diseases (AITD)¹⁴. In AITD, genetic variant transcripts of NLRP1, such as rs6502867, have been implicated in thyroid inflammation. These variants dysregulate the immune response directed at thyroid epithelial cells, promoting chronic inflammation and tissue destruction. Unlike vitiligo, this inflammation does not target melanocytes, but rather thyroid cells.¹⁵ Furthermore, studies have shown that NLRP1 contributes to the pathogenesis of Psoriasis⁶. Certain genetic variant transcripts of NLRP1 are upregulated in patients with Psoriasis, a chronic inflammatory skin disorder. In psoriasis, genetic variant transcripts in NLRP1 (e.g., rs878329) have been associated with excessive immune responses. Unlike vitiligo, psoriasis targets keratinocytes and results in an overproduction of skin cells.¹⁶Rheumatoid Arthritis (RA) is another autoimmune condition that has been linked to the NLRP1 gene. Genetic susceptibility studies have identified potential links between NLRP1 polymorphisms and this disease. Variants of NLRP1 contribute to the autoimmune responses and chronic inflammation characteristic of RA through tissue damage. In RA, the genetic variant of NLRP1 (rs2670660), attacks the synovial tissue and causes joint pain.¹⁷.

Methods

The research was conducted through a traditional literature review of relevant articles in the field of inflammation in Vitiligo. The review aimed to identify and analyze studies that provided an outline for NLRP1 as a crucial inflammasome in Vitiligo.

A search was conducted of the following databases: Google Scholar, PubMed, and the NIH website. The search was performed using literature from October 10, 1960 to October 10, 2023.

Inclusion criteria included studies that were experimental, clinical trials, or comprehensive reviews on the NLRP1 inflammation or its relevance to Vitiligo. The search strategy included a combination of keywords and controlled vocabulary terms surrounding the topic of NLRP1 and inflammation in Vitiligo. Specifically, articles written in the English language were considered. Additionally, articles that specifically focused on the inflammasome’s role in skin diseases or autoimmune diseases, Vitiligo, were prioritized. Exclusion criteria included studies that were not involved in the body’s inflammatory process or with autoimmune diseases. Additionally, research studies that lacked sufficient data to process into this review were excluded.

Data extraction included studying the methodology and process of the article. Additionally, any interventions or treatments used in relevance with NLRP1 or Vitiligo were taken into consideration for this review. Finally, the primary outcome of the study was examined in each paper (e.g. levels of inflammatory markers, progression of Vitiligo, and therapeutic responses).

Results

Vitiligo is a chronic autoimmune skin condition which can develop due to a combination of genetic and environmental factors. Certain genetic variations influence immune regulation and response, making individuals more prone to developing autoimmune conditions like vitiligo. A large majority of immune traits are influenced by our genes, this means parental genetic contributions play a major role in susceptibility to this autoimmune disease. Environmental factors, such as exposure to certain chemicals, stress, or infections, also contribute to the triggering of vitiligo in genetically predisposed individuals.

The depigmentation of the skin and premature whitening of natural body hairs profoundly affects individuals with vitiligo, however, the precise mechanisms underlying this condition’s attack on melanocytes require further investigation. This condition affects millions worldwide, yet its molecular mechanism of action remains elusive.

Discussion

This investigation into the involvement of NLRP1 in inflammatory pathways in vitiligo displays the connection between genetic predisposition, immune dysregulation, and tissue-specific autoimmune responses. Vitiligo, a disorder characterized by the progressive loss of skin pigmentation due to the destruction of melanocytes, presents a challenge in both its etiology and treatment. While autoimmune mechanisms have long been implicated in vitiligo pathogenesis, the specific triggers driving the attack on melanocytes have remained incompletely characterized. 

The identification of NLRP1 as a potential key in vitiligo pathogenesis could represent an advancement in how we approach similar autoimmune-disorders. This discovery implicates an anomaly in immune signaling pathways, particularly inflammasome activation, during the destruction of melanocytes. By understanding the precise mechanisms behind NLRP1-caused inflammation in vitiligo, targeted therapeutic interventions aimed at reducing this inflammation to slow or stop the death of melanocytes could be developed.

Moreover, the broader implications of NLRP1 dysregulation extend beyond vitiligo to other autoimmune conditions. Genetic polymorphisms in the NLRP1 gene have been associated with susceptibility to autoimmune thyroid diseases, psoriasis, and rheumatoid arthritis. This underscores the importance of further investigating NLRP1-mediated inflammation and its contribution to autoimmune pathologies. Of course, beyond therapeutics, NLRP1 holds significance in Vitiligo and other related autoimmune conditions due to the prevalence of NLRP1 in the body. NLRP1 plays a crucial role in the body for each human and is critical such that research exploring its mechanisms could prodive breakthroughs in every field relating to the immune system. The potential therapeutic targeting of NLRP1 presents an opportunity in the management of autoimmune diseases. Gene therapy approaches aimed at regulating NLRP1 expression in order to restore immune balance and prevent autoimmune tissue damage. This could involve manipulating NLRP1 expression to restore immune balance. In patients in which NLRP1 is over-expressed, inhibition could be used to prevent heightened immune activation. NLRP1’s activity or expression is altered in vitiligo patients, therapeutic methods aiming to balance NLRP1’s activity spare the killing of melanocytes.

Currently, researchers are focusing on inhibiting the NLRP1 gene through drugs to treat inflammatory diseases.¹⁸A suggestion for future research on NLRP1 would be to shed light on the mechanisms that activate the gene in melanocytes, such as UV radiation or genetic factors. Moreover, research is needed to elucidate why NLRP1 is particularly active in melanocytes, this could be done through vitro models of melanocyte destruction where NLRP1 activation is simulated. The overarching goal of this research would be to provide a more stable base to start developing therapeutics. However, there are significant challenges in the targeting of NLRP1 as a therapeutic. Firstly, although inhibiting NLRP1 may reduce excessive inflammation in these diseases, doing this could also risk impairing the body’s natural immune response. Additionally, NLRP1 shares inflammatory pathways with other bodily inflammasomes such as NLRP3.¹⁹ Designing therapies that only affect NLRP1 are crucial in order to leave other life-dependent inflammasomes unaffected.

Conclusion

This paper aimed to provide an overview of vitiligo, a skin condition distinguished by a loss of skin color and patches of depigmentation. The disease affects approximately 1-2% of the global population, and is an autoimmune condition where autoreactive CD8+ T cells target and attack melanocytes, leading to apoptosis and a loss of melanin. The mechanisms triggering the immune response against melanocytes remain unestablished. A gene involved in the vitiligo immune response is the NLRP1 gene, crucial in the innate immune system, associated with inflammation regulation, and codes for the NLRP1 inflammasome. NLRP1 variants in individuals with vitiligo suggest a potential role of the NLRP1 inflammasome in the disease’s pathogenesis. Future research should focus on these NLRP1 variants that influence inflammasome activity and how they can cause melanocyte apoptosis. Exploring therapeutic options that can control NLRP1 activity, such as inflammasome inhibitors or gene-editing approaches, holds promise for developing treatments for vitiligo. Insight into the involvement of NLRP1 in vitiligo provides a foundation for further research and a deeper understanding of the mechanisms underlying Vitiligo.

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