He protec but he also attac – Inflammasomes swinging the sword

Abstract

This issue of the Biomedical Journal puts an emphasis on inflammasome subunits, the NLR protein family, and the role they play in immunity. CIITA is presented as promising tool for augmenting tumor immunogenicity. Several articles look into the involvement of NLRP3 in inflammatory bowel disease and changes of the gut microbiome, in blood glucose management, in sterile inflammation, and NLRP3's contribution to the development of hepatic encephalopathy. Furthermore, a review concerning small cell neuroendocrine carcinoma of the cervix is presented, insights are provided as to the association of knee pain and patellar malalignment, and the connection between hypoxia and sleep apnea in the case of liver injury is elucidated. Additional articles illuminate the challenge of predicting influenza infections; show how ctDNA may serve as predictor for survival outcome in ovarian carcinoma; and lastly soft tissue changes after bimaxillary rotational surgery are assessed.

Spotlight

From caveman cuisine to cosmic insights

Approximately 1–2 million years ago, early humans began to harness the power of fire to cook their food, which ensued a noteworthy transformation of their physical and cognitive nature. The once enormous jaw muscles were no longer essential for tearing into raw food since cooked food was much more easily digestible. The following weaker jawed generations were consequently able to survive the odds of natural selection. The newfound space within the jaw structure allowed for the expansion of the cerebral cortex, ushering in a novel epoch of cognitive abilities. Among these abilities, pattern recognition took a center stage. It conferred distinct advantages in terms of environmental perception, and thus improved survival skills. Eminent astrophysicist Neil deGrasse Tyson has postulated that the capacity for pattern recognition played a pivotal role in natural selection, enabling our ancestors to better discern prey from predators, distinguish toxic flora from nourishing plants and more.1 Facial pattern recognition stands out as a common example of pattern recognition. It has been proposed that this particular skill may be honed in children to such a degree that up to the age of 9 months, humans possess the remarkable ability to even discriminate the individual faces of animals such as apes.2 [1]

Pattern recognition is of paramount importance for the innate immune system. In order to safeguard the human body against viral and bacterial infections, the immune system has evolved a specialized pattern recognition molecule, the inflammasome. This issue of the Biochemical Journal puts an emphasis on the roles different subunits of the inflammasome play in immunity.

A half-life of two weeks

Swiss biochemist Juerg Tschopp once humorously remarked that the models developed in his lab had a lifespan of merely two weeks. Tschopp was renowned for his perpetual fascination with uncharted realms of biology. Early on he embarked on the journey of conceptualizing theoretical models for what he would later term the “inflammasome.” In 2002, his research group finally unveiled the existence of this intriguing multiprotein signaling platform [2].

Inflammasomes are cytosolic, multimeric protein complexes that form through assembly of pattern-recognition receptors (PRRs). They play an essential role in activating key components of the host's defense mechanisms, including inflammatory caspases and cysteine-dependent aspartate-directed proteases, which facilitate the maturation of inflammatory cytokines such as IL-1β and IL-18. Additionally, inflammasomes trigger a form of lytic cell death known as pyroptosis. The initiation of inflammasome activation is triggered by an array of cytosolic PRRs, responding to either microbe-associated molecular patterns (MAMPs) or host-derived danger-associated molecular patterns (DAMPs). Cytoplasmic PRRs involved in inflammasome assembly encompass nucleotide-binding oligomerization domain-like receptors (NOD-like receptors), also known as nucleotide-binding leucine-rich repeat-containing receptors (NLRs). A prime example is the well-studied NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which responds to a diverse array of molecular patterns, including asbestos, amyloid aggregates, and uric acid [[3], [4], [5]].

Putting a red flag on tumor cells

In their comprehensive review, Forlani et al. delve into the complex world of the MHC class II transactivator (CIITA), a pivotal orchestrator in the gene expression of major histocompatibility complex class II (MHC-II), and a member of the heterogeneous NLR protein family [6]. While CIITA's well-established role revolves around the transcriptional regulation of MHC genes, it extends its influence over a constellation of more than 60 immunologically crucial genes, including the likes of IL-4 and IL-10 [7]. Beyond its transcriptional regulatory function, CIITA steps in as antiviral restriction factor at the front of intrinsic immunity, taking up the arms against viral replication and assembly of human retroviruses. By governing both intrinsic and adaptive immunity, CIITA exerts a dual responsibility that positions it in a league of its own. It furthermore makes an appearance as a promising tool for augmenting tumor immunogenicity [8,9].

In the current BMJ issue, Forlani et al. discuss CIITA's discovery, structure, and multifaceted functions, while advocating its central role in advancing our comprehension of the fundamental mechanisms underpinning adaptive immunity. Recently found knowledge reveals a profound implication in the context of tumor biology: most tumor cells go unnoticed by tumor-specific T helper cells since they do not express MHC-II molecules due to an absence of CIITA. However, involving CIITA opens up an exciting avenue wherein modified tumor cells can closely emulate physiological MHC-II expression, paving the way for innovative anti-tumor vaccination strategies [Fig. 1] [6].

Fig. 1.

Anti-tumor immunity could be transferred to syngeneic naïve recipients by adoptive cell transfer of immune cells. CIITA modified cancer cells are set up to express functional MHC class II molecules in a physiological fashion. Purified and selected tumor-specific peptides can then be used to craft a vaccine cocktail for therapeutic purposes [6].

Also in this issue

VSI: NLRs – Review articles

Inflammaging in IBD

Inflammatory bowel disease (IBD) evolved into a global phenomenon, with its prevalence rapidly increasing in newly industrialized nations undergoing westernization. IBD includes a group of chronic systemic inflammatory conditions such as Crohn's disease and ulcerative colitis, both of which are associated with significant morbidity. Technology has assumed a major role in the management of IBD, with smartphone applications enabling patients to monitor their diet, bowel movements, or even locate the nearest restroom while traveling. The healthcare burden imposed by IBD is substantial, not counting in the social stigma and a diminished quality of life often experienced by affected individuals [[10], [11], [12]].

The precise cause of IBD remains elusive. It is thought to be connected to an abnormal immune response against gut microbiota triggered by environmental factors in genetically susceptible individuals [13]. The gut microbiome functions as a metabolic organ and performs various physiological functions contributing to human health. Disturbances in its balance may both contribute to and result from intestinal inflammation [14]. Recent evidence suggests that IBD patients exhibit signs of inflammaging, a chronic inflammatory state that intensifies with age, potentially conveyed by mechanisms such as NLRP3 inflammasome activation [15,16]. Furthermore, individuals with IBD face an increased risk of developing colorectal cancer (CRC) [17].

Morrison et al. dig into the potential of NLR proteins as biomarkers for disease detection and as targets for drug development. NLRs are involved in NF-κB-mediated inflammation, and their dysregulation has been documented in both IBD and CRC patients. Targeting NLRs holds the promise of advancing research toward the development of treatment strategies with long-term efficacy against IBD conditions [18].

A cocktail of postbiotics

Changes in the gut microbiome have been demonstrated to initiate subsequent metabolic effects linked to the advent of obesity and metabolic syndrome [19]. In their thorough review, e-Lacerda and colleagues explore the mechanisms by which bacterial sensors within the innate immune system transmit signals from bacterial elements such as postbiotics, thereby influencing host metabolic inflammation in contrasting manners. Notably, Nod1 and Nod2 both enlist receptor-interacting protein kinase 2, eventually however yielding opposite effects on blood glucose regulation. NLR family pyrin domain containing (NLRP) inflammasomes generate divergent metabolic responses, with obesity fostering conditions that favor the activation of pro-inflammatory reactions mediated by NLRP3. The team proposes the incorporation of short-acting postbiotics as means to engage protective adaptive immune responses, and facilitate sustained enhancements in blood glucose management [20].

DAMPing down sterile inflammation

As previously elucidated, the NLRP3 inflammasome assumes a key role in the context of antiviral immune responses. Activation of this complex ensues upon detection of cytosolic danger signals, including but not limited to mitochondrial injury, protein aggregates, and aberrant ion concentrations, all of which can manifest as consequences of viral infections [21]. Conversely, sterile inflammation transpires in the absence of microbial agents and is intimately linked to the recognition of intracellular constituents released from damaged and necrotic cells. Specifically pattern recognition receptors such as toll-like receptors (TLRs) and NLRs play an active role in bringing about sterile inflammatory responses. Sterile inflammation has been correlated with pathological conditions, such as elevated levels of tissue damage arising from ischemia-reperfusion injury in myocardial infarction, atherosclerosis, and Alzheimer's disease [22].

Cho, Ying, and Sweeney embark on exploring the role of sterile inflammation, a response triggered by DAMPs, in the genesis and progression of cardiometabolic disorders. Their hypothesis suggests that targeting NLRP3 itself could reveal therapeutic means capable of mitigating the adverse downstream effects of NLRP3 activation. Thus, it would be feasible to reduce the effects of NLRP3 activation including the development of cardiometabolic ailments such as obesity, diabetes, non-alcoholic steatohepatitis, and others [23].

VSI: NLRs – Original articles

High levels of ammonia

Urgent action is imperative to achieve rapid decarbonization in order to prevent global temperatures from exceeding a 1.5 °C increase above pre-industrial levels. A range of approaches has been proposed to avert the dire consequences of climate change, that increasingly threaten the well-being of current and future generations including droughts, storms, heatwaves, wildfires, melting glaciers, and rising sea levels. A significant aspect of this effort comprises the reduction of greenhouse gas emissions stemming from the combustion of fossil fuels. At the same time the rising demand of a society that transitions to more electrification has to be met.3^,4 Ammonia is gaining interest as a capable candidate for fueling various applications, including transportation, energy production, and heating for decades. While ammonia currently lags behind conventional fossil fuels in terms of advantages, key industries are actively exploring its potential to become a safe and viable energy source, positioning it as a major player for a cleaner future [24].

In their research, Cheon et al. conducted both in vivo and in vitro studies to investigate the role of the NLRP3 inflammasome in the development of hepatic encephalopathy (HE). Their findings demonstrate that the hyperammonemia associated with HE triggers an overproduction of mitochondrial reactive oxygen species, and subsequently leads to the activation of the NLRP3 inflammasome [25].

The gut microbiome not vibing with an active NLRP3 inflammasome

In accordance with a previously presented review authored by Morrison et al., there is promise in considering the NLR family as a potential therapeutic target for managing IBD [18]. Wang et al., however, have a more specific focus on the direct inhibition of the NLRP3 inflammasome, aiming to modulate IBD and reshape the composition of the gut microbiota. In their study, the team assessed NLRP3 expression in the colons of individuals with IBD. They furthermore examined IBD-like symptoms in a dextran sulfate sodium (DSS) induced colitis mouse model. The mice were treated with an agent designed to inhibit the NLRP3 pathway. The correlation analysis conducted in the study strongly suggests that the inhibition of the NLRP3 inflammasome has the potential to alleviate IBD-like symptoms by regulating the gut microbiome [26].

Review articles

Raising awareness for SCNECC

The World Health Organization (WHO) classifies neuroendocrine tumors (NETs) into three grades based on mitotic count and the Ki-67 cellular proliferation marker.5 Cervical cancer ranks as the fourth most prevalent cancer in women globally,6 and it is alarming that women in a number of countries experience significant delays in seeking healthcare once symptoms manifest. These delays may be attributed to insufficient awareness among individuals regarding abnormal gynecological conditions, and furthermore a lack of diagnostic and treatment capabilities within healthcare facilities. A majority of cervical cancer is due to human papillomavirus (HPV).7 [27]

Occasionally, high-grade NETs can arise outside of the most common primary tumor locations, including the female genital tract. Among these, the aggressive small cell neuroendocrine carcinoma of the cervix (SCNECC) stands out as a rare and particularly unfavorable form of invasive cervical malignancy. Chao et al. have undertaken a comprehensive review of various clinical management approaches for this type of carcinoma. They point to the dearth of clinical trials and evidence-based treatment guidelines, emphasizing the therapeutic challenges this knowledge gap poses. The combination of immune checkpoint inhibitors and chemoradiation surfaces as gateway for improving outcomes in SCNECC patients. Chao et al. advocate for the establishment of collaborative efforts, such as a dedicated biobank for SCNECC [28].

Featuring kneecaps

Until recently, the prevailing assumption was that kneecaps evolved in tandem with the emergence of egg-laying tetrapods on land. The intricate functionality of the patella has long perplexed scientists, prompting questions such as why elbow caps don't exist, and why double-kneecaps are unique to ostriches. However, in 2017, a groundbreaking discovery challenged the original notion, suggesting that kneecaps may have a much older origin. Researchers have advanced the idea, that approximately 400 million years ago frogs may have been among the earliest creatures featuring kneecaps.8^,9 [29]

In his review, Wu examines knee pain resulting from patellar malalignment (PM). The primary contributing factor often lies in an imbalance within the soft tissues surrounding the patella. The author advocates for non-surgical interventions as the initial approach, as they consistently lead to high patient satisfaction rates. Nevertheless, advancements in surgical techniques also demonstrated encouraging outcomes. Rather than concentrating solely on isolated structures like the tibiofemoral or the patellofemoral joint, a broader perspective should be taken into account for PM management [30].

Original articles

Having a closer look at hypoxia

From a historical perspective, freediving can be traced back to the dawn of humanity. It has been practiced across the ages and spanning the globe. Freediving served various purposes such as hunting, pearl diving, sponge collection for cosmetic and contraceptive use. Later on it was a means to aid in salvaging valuable items from shipwrecks, and also employed in military operations.10^,11

One remarkable group of people, the Sama, that reside in maritime Southeast Asia, stands out for their freediving abilities. Members of the Sama are able to hold their breath for astonishing durations of up to 13 min while diving to depths of 60 m. The physiological response during these dives resembles acute hypoxia, offering valuable insights into the medical condition. Unfortunately, the traditional sea nomadic way of life is under grave threat as these real-life aquamen and aquawomen face marginalization and a lack of equal citizenship rights, prompting many to abandon their traditional lifestyle close to the sea.12^,13

In a study conducted by Ji et al., the focus shifts to understanding the connection between intermittent hypoxia and hepatic steatosis in mice, shedding light on the role of obstructive sleep apnea (OSA) in the development of non-alcoholic fatty liver disease. The team's research supports the hypothesis that intermittent hypoxia associated with OSA contributes to liver injury by differential regulation of the hepatic expression of fatty acid translocase (CD36) in both lean and diet-induced obese mice [31].

Seasonal influenza infection on the radar

In the year 1918, a devastating influenza pandemic caused by the virus subtype H1N1 unfolded in three distinct waves. This infamous outbreak, commonly referred to as the Spanish flu, emerged in March of that year. The first wave, although relatively mild, took place during the summer, while the most deadly wave struck during the subsequent winter. The toll exacted by this pandemic was staggering with an estimated 20 to 40 million lives lost, surpassing the casualties of World War I, and even eclipsing in one year the death toll of four years of Bubonic Plague in the 14th century.14

Also in current times seasonal influenza remains a significant threat, particularly in terms of respiratory illnesses associated with the flu. Timely diagnosis and early intervention are crucial, yet the clinical diagnosis of influenza remains challenging [32].

Past hypotheses have suggested that seasonal variations in the Earth's geomagnetic field may influence human health, potentially leading to periodic surges in infectious and chronic diseases [33].

Hung et al. have made significant strides in this field by developing and comparing machine learning algorithms based on clinical features. These algorithms have demonstrated satisfying levels of accuracy in predicting influenza infections among patients presenting with influenza-like symptoms in emergency departments. The researcher's model has outperformed previously established conventional models, and the team is optimistic that with further refinement, their approach could prove invaluable in the ongoing battle against infectious diseases, including the new era of COVID-19 [32].

Needle in a haystack

Ovarian cancer stands as one of the most lethal gynecological malignancies. Its nature is complicated due to the existence of diverse subtypes, along with the complex interplay of inter-tumoral and intra-tumoral heterogeneity. Inter-tumoral heterogeneity encompasses genotypic and phenotypic variations emerging among multiple tumors of the same type within a single patient. In contrast, intra-tumoral heterogeneity arises from clonal expansion driven by genetic modifications from somatic mutations, stochastic genetic changes, or epigenetic alterations [34]. Heterogeneity may significantly impede the effectiveness of treatment, particularly when a clone carrying a drug-resistant mutation remains undetected during biopsy. Circulating tumor DNA (ctDNA) is apt to provide invaluable information by serving as a biomarker for cancer diagnosis, treatment, and monitoring. It even allows for real-time tracking of multifocal clonal evolution. Although the detection of ctDNA is a formidable challenge due to its high fragmentation and low concentration, various methods have been developed to identify ctDNA not only in blood samples but also in non-blood sources such as urine, cerebrospinal fluid, pleural or peritoneal fluid, saliva, stool, and seminal fluid [[35], [36], [37]].

In their study, Chao et al. investigated whether mutations in plasma ctDNA could offer prognostic insights for patients with diverse histological types of ovarian carcinoma. The team compared blood samples collected both before and after surgery. It was found that the presence of ctDNA mutations after surgery served as independent predictor for less favorable progression-free survival and overall survival outcomes [38].

Changes in tissue after dental surgery

While evidence of dental treatments can be traced back to ancient civilizations such as the Egyptians, Greeks, Etruscans, and Romans – with the oldest known instance of a tooth filling dating back 13,000 years – it took many centuries for dentistry to evolve into a distinct profession. During medieval Europe, a papal decree prohibited individuals in holy orders from practicing medicine. Consequently, monasteries, which often provided medical services to their communities, enlisted the expertise of barbers. This group of professionals were accustomed to working with sharp instruments and trained in minor surgical procedures. This gave rise to a novel profession known as barber surgeons. These practitioners offered a wide range of services, from haircuts to amputations. Additionally other tradespeople who possessed the available tools and brute strength like blacksmiths or shoemakers, would also offer to extract teeth for a fee. Unfortunately, their lack of comprehensive knowledge of anatomical structures often resulted in damage to surrounding tissues and structures.15^,16^,17

Within Asian populations, skeletal class II deformities are quite common. The preferred method for correcting these issues involves bimaxillary rotational surgery with mandibular setback, chosen for its superior aesthetic results and stability. Keardkhong et al. conducted a prospective study to compare regional soft tissue changes in patients with class III overbite and open bite deformities who underwent bimaxillary rotational surgery with a clockwise or counter-clockwise mandibular setback. Utilizing 3D imaging analysis, the research team determined that postoperative soft tissue changes were similar between both patient groups, with the exception of the upper lip, lower lip, and chin [39].

Disclaimer

None.

Conflicts of interest

The author declares no conflict of interests.