The scientific evidence of “inflammasome” existence dates back to 2002, when a caspase-activating complex composed of the NLR (nucleotide-binding oligomerization domain, Nod-like receptor) protein, the adaptor ASC (apoptosis-associated speck-like protein containing a CARD) and pro-caspase-1 was identified [
13]. Several types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections, cell damage and other stressors, such as metabolic imbalances. Inflammasomes are composed of a sensor, such as pyrin domain containing related protein family (NLRP), absent in melanoma (AIM) 2, CARD domain containing (NLRC) 4, the adaptor ASC and caspase-1. While NLRP1, NLRP3, NLRP6, NLRP7, NLRP12 and AIM 2 depend critically on ASC for the engagement of caspase-1, the inflammasome sensor NLRC4 can directly interact with caspase-1. The regulated activation of inflammasomes after microbial infection or injury is critical for the maintenance of tissue homeostasis, and deregulated inflammasome activity has emerged as a major contributor to the pathogenesis of prevalent diseases, including inflammatory bowel disease, coronary heart disease, autoimmune diseases, neurodegenerative diseases and cancer [
14]. Together with Toll-like receptors (TLRs) [
15], NLRs belong to the innate immune pattern recognition receptors (PRRs), which are responsible for the recognition of pathogens or tissue injuries through pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), respectively [
16]. The culminant event is the production of active caspase-1 able to process prointerleukin-1β (IL-1β) into the mature protein IL-1β. Progressively, inflammasomes have attracted scientific interest, and nowadays, they are considered crucial mediators of inflammation. Currently, NLRPs, AIM2, IFI (interferon-γ inducible factor) 16 and RIG-I inflammasomes have been characterized [
17]. The NLRP3 inflammasome is the most studied one. Its role has been characterized first in a subset of rare autoinflammatory conditions [
18] and, subsequently, in inflammatory [
19,
20,
21,
22,
23] and metabolic diseases [
24]. In contrast, the mechanism of action of other inflammasomes such as NLRP7 [
25] and IFI16 [
26], have been more recently described. In particular, NLRP7 has been shown to assemble an ASC and caspase-1-containing high molecular weight inflammasome complex in response to bacterial lipopeptides, with a molecular mechanism involving ATP binding and direct ATPase activity [
25]. Instead, IFI16 [
26] and AIM2 [
27] are involved in inducing a caspase-1-activating inflammasome formation by recognizing viral DNA in the nucleus or cytosol, respectively. A recent study identified a mechanism by which AIM2 inflammasome activity is negatively regulated by TRIM11 (tripartite motif 11), determining its degradation via selective autophagy upon viral infection [
28]. Recently, novel significantly divergent functions for NLRPs have been identified, in addition to their already well-established proinflammatory functions. This is especially true for NLRP12 and NLRP4. NLRP12 was first described 10 years ago, when a seminal study demonstrated its role as a negative regulator of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway [
29]. NLRP12 plays a crucial role in both the hematopoietic and nonhematopoietic compartment for controlling overt inflammation, colitis and colitis-associated tumorigenesis. The absence of NLRP12 in mice resulted in a severe uncontrolled inflammation that rendered NLRP12-deficient mice highly susceptible to experimental colitis and inflammation-induced tumorigenesis [
29]. NLRP4 (a member of the NLR family of the cytosolic receptor strongly expressed in several tissues [
30]) has recently been reported as a negative regulator of autophagy and type I IFN signaling, resulting from the interaction of its NACHT domain with Beclin1 and TANK-binding kinase 1 (TBK1), respectively [
31]. Furthermore, NLRP4 was identified as an inhibitor of tumor necrosis factor (TNF)-α- and IL-1β-mediated NF-κB activation, which is achieved through an interaction with IKKα. The pyrin domain (PYD) of NLRP4 is necessary for this inhibitory effect on NF-κB, underscoring its importance as a critical regulator of inflammatory signaling pathways [
32]. Moreover, recent literature frames NLRP4 as an important key mediator during the immune response to viral infections [
33].
During the last decades, there has been an explosion in the research field of inflammasomes; the majority of research articles were aimed at the characterization of inflammasomes in noncancerous diseases, ranging from autoimmune diseases, such as arthritis [
34,
35,
36] and lupus [
37,
38], to neurodegenerative [
39,
40], renal [
41,
42,
43] and vascular diseases [
44,
45]. The main efforts at dissecting inflammasome mechanisms of action came from studies using murine or cell models of fungal [
46,
47,
48,
49,
50], bacterial [
51,
52,
53,
54,
55,
56], viral [
57,
58,
59,
60,
61] and prion infections [
62]. On the one hand, by using animal and cell models, the function of each unit of the inflammasome apparatus can be assessed manipulating its expression. On the other hand, genetic studies uncovering mutations or genetic variants in inflammasome components, conferring the susceptibility for diseases such as diabetes and systemic inflammation [
63], provided the complementary side of this intrinsically complex picture. A recent review highlighted the importance of inflammasome-related genes in several major human diseases, by molecular and genetic networks, based on genome-wide association studies [
64]. Increasingly available large Omics and clinical data, in tandem with system biology approaches, have offered the opportunity to study more comprehensive and dynamic molecular inflammation networks, showing a double-sword role of inflammasomes. A recent study identified 12 expression profiling datasets derived from nine different tissues isolated from 11 rodent inflammatory disease models related to common chronic diseases. The overlapping of inflammasomes with the innate immunity genes generated a list of six common complex diseases, including obesity, type II diabetes, coronary heart disease, late-onset Alzheimer’s disease, Parkinson’s disease and sporadic cancer [
65]. The crucial crosslink between inflammasomes and immune-related diseases is the activation of IL-1β; immune stromal and tumor cells can produce IL-1β, which also stimulates the expression of cyclooxygenase (COX)-2, IL-6 and chemokine C-C motif ligand (CCL) [
66].
Although the importance of IL-1β in cancer is without doubt, the list of its cellular targets is still partially defined. T lymphocytes and myeloid cells are established downstream targets of IL-1β; in myeloid cells, IL-1β activates the NF-κB pathway through binding to its receptor, IL-1RI [
67]. The ability of IL-1β in inducing angiogenic pathways, which trigger tumor progression, has been widely reported [
68], although the mechanisms through which this event occurs have not been completely defined. Due to the relative novelty of this topic, scientific reports dissecting the role of inflammasomes in carcinogenesis are still a minority, compared to infectious and autoimmune diseases. In fact, a plethora of scientific works have been aimed at the characterization of inflammasomes in melanoma [
69], leukemia [
70] colon [
71,
72], oral [
73] and colitis-associated [
74] cancers. Products of inflammasome activation (IL-1β and IL-18) behave as protumorigenic factors in gastrointestinal cancers, while the protective role of NLRP6 against tumor development has been clarified [
75], whereas, for NLRC4, contrasting findings were reported [
76,
77]. A constitutive activation of the NLRP3 inflammasome in late-stage human melanoma cells with the autonomous secretion of active IL-1β has been demonstrated [
78]. Knockout mice for IL-1β have reduced the angiogenesis and growth of melanoma tumors [
79]. The treatment of metastatic human and mouse melanoma cell lines with the anti-inflammatory phytochemical thymoquinone was shown to hamper the metastasis process by inhibition of the NLRP3 inflammasome [
80]. Nonetheless, in hepatocellular carcinoma, the loss in expression of the NLRP3 inflammasome components, both mRNA and protein, was demonstrated and correlated with cancer progression [
81].