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Inflammasome and Pyroptosis in Hypertension: History
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Subjects: Pathology
Contributor: Santiago Cuevas

Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane.

  • hypertension
  • pyroptosis
  • inflammasome
  • inflammation

1. Inflammation and Hypertension

Elevated blood pressure, defined as a systolic pressure higher than 130 mmHg and diastolic pressure greater than 80 mmHg [1], is the leading risk for cardiovascular and kidney diseases [2] and was reported to affect 1.13 billion people in the world in 2016 [3]. As a consequence, high blood pressure is a leading cause of death worldwide [4] and research in the field of hypertension is highly dynamic. Extensive evidence demonstrates an important role of inflammation in the pathogenesis of hypertension and vascular and kidney diseases. A series of elegant studies performed by Grollman et al. in the 1960s first evidenced that autoimmune factors play a critical role in an animal model of renal infarction-induced hypertension [5][6]. The same group also reported that hypertension could be transferred to normotensive rats by transplanting lymph node cells from rats with renal infarction hypertension [7]. In the 1970s, Svendsen revealed that an intact thymus is required for the maintenance or development of hypertension in three different animal models of the disease: the deoxycorticosterone acetate (DOCA) salt model [8], mice with partially infarcted kidneys [9], and the genetically hypertensive NZB/Cr mouse strain [10].

Since those early studies, investigation of the interplay between inflammation and high blood pressure has grown exponentially, and more than 18,000 publications have explored this topic to date. It is now widely acknowledged that low-grade or persistent inflammation is a key player in the development and maintenance of hypertension. Exhaustive research demonstrates the infiltration of immune cells, like T cells, macrophages, and dendritic cells in the kidneys, perivascular fat, or heart during the development and progression of hypertension [11][12][13][14][15][16][17][18][19][20][21][22][23][24]. In particular, immune cell transfer studies performed by Guzik et al. [15] demonstrated that the development of angiotensin II-induced and DOCA salt-induced hypertension was dependent on the presence of T cells. Moreover, pharmacological inhibition of immune cells with, for instance, mycophenolate mofetil, tacrolimus, or cyclophosphamide attenuates the development of high blood pressure [25][26][27][28][29]. More recently, the genetic ablation of certain immune cells and specific receptors on immune cells or cytokines demonstrates that activation of immune cells like T cells, macrophages, and dendritic cells [18][23][30][31][32][33][34][35] is essential for the development of elevated blood pressure. Lately, B cells have also been reported to be important in the development of hypertension [36]. The role of immune cells from the adaptive and innate arms of the immune response as well as different cytokines in hypertension has been extensively reviewed elsewhere, and thus, we will not review it here [37][38][39][40][41][42].

As mentioned above, inflammatory cells have been repeatedly demonstrated to infiltrate organs involved with blood pressure regulation, including the vasculature, the kidneys, and the brain [40][43][44], during hypertension. For instance, in a hypertensive kidney, macrophages and T cells localize around glomeruli and arterioles and within the interstitium [45][46]. Similarly, infiltration of immune cells and increased levels of inflammatory mediators have been demonstrated in the perivascular fat of large arteries and arterioles in animal models of hypertension [45]. Activated inflammatory cells produce and release cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-17, IL-6, and interferon-gamma (IFN-γ) that are known inducers of renal and vascular dysfunction [33][34][35][47][48][49]. Many of those inflammatory mediators are known to stimulate fibrosis [47][50][51], for instance, which is seen in both vessels and kidneys of hypertensive patients and animal models of the disease. In addition, T cells and macrophages contain all the machinery needed for the production of vasoactive molecules such as angiotensin II [52][53][54], endothelin-1 [55][56], or prostaglandins [57][58], which are known mediators of hypertension and hypertension-induced end-organ damage. Moreover, a number of inflammatory factors released by activated immune cells can also modulate the local production of angiotensinogen and, later, angiotensin II generation within the kidneys, vasculature, or nervous system [51][59][60]. This implies that inflammatory cells increase the local levels of pro-hypertensive stimuli and can further increase blood pressure by stimulating fluid retention and vascular constriction [61]. Interesting animal studies have also shown that IL-17 or IFN-γ deficiency is associated with alterations of sodium (Na+) transporters in the kidneys and, consequently, reduced Na+ retention in hypertensive conditions [62]. Despite all this evidence linking immune cell infiltration and the development and progression of hypertension, the exact mechanisms that trigger low-level inflammation observed in the elevated blood pressure setting still remain unclear.

2. Inflammasomes and Pyroptotic Cell Death

Inflammasomes are essential players in the inflammatory response and one of the first steps for the initiation of chronic low-grade inflammation. Inflammasomes are intracellular protein oligomers that are sensors for pathogens, tissue injuries, and recognition of the signals altering homeostasis. They are composed of an effector protein, an adaptor protein, and a sensor protein that oligomerize in a large complex after activation. The inflammasome sensor protein is usually a pattern recognition receptor (PRR) that oligomerizes after activation induced by pathogen-associated molecular patterns (PAMPs), endogenous host-derived damage-associated molecular patterns (DAMPs), or homeostasis-altering molecular processes (HAMPs) [63]. Three families of sensor proteins have been described, belonging to the nucleotide-binding domain, leucine-rich-containing family of receptors (NLRs), the absent in melanoma 2-like receptors (ALRs) or pyrin, which give name to the inflammasome and share analogous structural domains. Moreover, there are several types of inflammasomes, such as NLRP1b (mouse), NLRP3, NLR family CARD domain-containing protein 4 (NLRC4), NLRP6, NLRP9, pyrin, and absent in melanoma (AIM) 2. A great variety of molecules activate different sensor proteins, including Bacillus anthracis for NLRP1b, Salmonella typhimurium for NLRC4, lipoteichoic acid for NLRP6, viral dsRNA for NLRP9, dsDNA for AIM2, toxin-induced modifications of Rho GTPases for pyrin, and several PAMPs, DAMPs, and HAMPs for NLRP3 [64]. After activation, the sensor protein oligomerizes and recruits the adaptor protein apoptosis-associated speck-like protein with the caspase recruitment domain (ASC) forming large filaments by prion-like oligomerization [65]. ASC filaments recruit the effector zymogen pro-caspase-1 by caspase activation and recruitment domain (CARD)–CARD homotypic interaction, facilitating its autoactivation by close proximity [66]. However, other inflammasomes can be activated without involvement of ASC, such as NLRC4 [67]. Activated caspase-1 induces the cleavage of gasdermin D and releases its lytic N-terminal domain (GSDMDNT) [68][69] from its C-terminus repressor domain to form pores in membranes. GSDMDNT lyses mammalian cells by acting from the inside of the cells and also has anti-bacterial activity [70]. Studies of the full-length crystal structure of GSDMD reveals distinct features of auto-inhibition among the gasdermin (GSDM) family members [71]. Released GSDMNT domains bind to negatively charged membrane lipids like phosphatidylinositol phosphate, cardiolipin, and phosphatidylserine [72]. Caspase-1 activation also mediates the proteolytic cleavage of the inactive precursor cytokines pro-IL-1β and pro-IL-18 to produce their active forms that are mainly released by GSDMD pores, which have a diameter of 10–14 nm and are big enough to release the mature form of these cytokines [70] (Figure 1). The GSDMD pore consists of about 54 N-terminal gasdermin subunits with a radical conformational change compared to their conformation in the full GSDM sequence, with extensive interactions among the inserted β-strands and the α-helix 1 localized in the globular domain [73]. Upon permeabilization of the plasma membrane by GSDMD pores, cells undergo a lytic, pro-inflammatory cell death known as pyroptosis that further promotes and increases the release of mature IL-1β and IL-18 and the induction of a pro-inflammatory environment [74]. If gasdermin pores at the plasma membrane are not repaired, pyroptosis will end with a burst in pro-inflammatory cytokine release and the discharge of large intracellular components (such as inflammasome oligomers or high mobility group box 1 (HMGB1) among others), resulting in a highly pro-inflammatory cell death process [68]. Unlike other programmed cell deaths, pyroptosis has been described as a strategy to preserve the inflammatory response through the release of pro-inflammatory intracellular content during plasma membrane permeabilization [75][76][77], a process that recruits immune cells to combat invading infectious organisms and promote tissue healing [78]. Pyroptosis was initially reported in macrophages infected with Salmonella typhimurium [79], but later it was also demonstrated in other cell types and in response to different signals [80]. Since then, pyroptosis has been associated with multiple diseases such as cardiovascular, liver, kidney, inflammatory, and immune diseases or cancer [81].

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Figure 1. Activation of the inflammasome and pyroptosis induce hypertension. In the first step of the inflammasome activation, pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) stimulate toll-like receptors (TLR) and the translocation of nuclear factor kappa B (NF-κB) to the cell nucleus, which, in turn, increases the transcription of the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome sensor, its posttranscriptional modification, and expression of pro-interleukin (IL)-1β and pro-IL-18. The second signal such as crystalline particles or P2X purinergic receptor 7 (P2 × 7) activation via ATP induces the oligomerization of the NLRP3 inflammasome complex which leads to the activation of caspase-1. Caspase-1 cleaves gasdermin D and converts pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18. Pyroptosis occurs by the insertion of the N-terminal fragment of gasdermin D into the plasma membrane, creating oligomeric pores and allowing for the release of pro-inflammatory cytokines such as IL-1β and IL-18 to the extracellular space. Pore formation also induces water influx into the cell, cell swelling, and osmotic cell lysis which induce further inflammation and hypertension by releasing more inflammatory products from the intracellular space. HMGB1: high mobility group box 1; IκB: inhibitor of κB; LDH: lactate dehydrogenase.

In humans, GSDM family members are composed of 6 members: GSDMA, B, C, D, E, and Pejvakin (PJVK), and all have a highly conserved N-terminal domain that induces pyroptosis when expressed ectopically, except for PJVKNT [68]. Pyroptosis depends on different innate immune pathways leading to GSDMD processing. Caspase-1 is one of the most studied proteases involved in pyroptosis by GSDMD cleavage. However, GSDMD cleavage and pyroptosis are also executed by other inflammatory caspases: human caspase-4 and -5 and mouse caspase-11 [80][82]. Moreover, other caspases (like apoptotic caspase-3 or -8) and proteases (like elastase or granzyme) can also elicit processing of GSDMB, D, and E and induce pyroptosis [83].

NLRP3 is the most studied member of the inflammasome family as it has been implicated in the pathophysiology of several autoinflammatory syndromes [84] and other diseases associated with metabolic, degenerative, and inflammatory processes [85]. Activation of the NLRP3 inflammasome can be induced in two different manners: the “canonical” and “non-canonical” pathways.

Canonical NLRP3 inflammasome activation begins with a priming signal driven by several classes of receptors facilitating the upregulation of NLRP3 and pro-IL-1β via nuclear factor kappa B (NF-κB) signaling and also key post-translational modifications of NLRP3. An activation signal is then initiated by PAMPs, DAMPs, or HAMPs, inducing physiological changes that are detected by NLRP3 and followed by the recruitment of ASC and caspase-1 to form the inflammasome complex [86]. Among the activators of this cascade, our group found different microorganisms, bacterial pore-forming toxins, hemozoin, or even melittin [87][88]. NLRP3 can also be activated by the phagocytosis of particulate matter (silica, alum, asbestos, uric acid crystals, cholesterol crystals, or β-amyloid deposits) as well as by cell swelling [89] or extracellular adenosine triphosphate (ATP) acting through the P2X purinoceptor 7 (P2X7) [90]. This activation signal islinked to mitochondrial dysfunction, lysosomal destabilization or plasma membrane damage, which result in cell metabolic changes, reactive oxygen species (ROS) formation, potassium (K+) and chloride (Cl–) efflux, and calcium (Ca2+) influx [91]. Although the exact mechanism leading to NLRP3 activation is not well-known, K+ efflux is a common initial step for NLRP3 activation in response to most of the triggers [92][93].

In the non-canonical inflammasome pathway, gram-negative bacteria activate the toll-like receptor 4 (TLR4)–toll IL-1 receptor (TIR)-domain-containing adapter-inducing interferon (IFN)-β (TRIF) signaling pathway leading to type I IFN production and upregulation of guanylate-binding proteins (GBPs) and immunity-related GTPase family member B10 (IRGB10), which in turn target outer membrane vesicles (OMVs) or bacterial and vacuolar membranes to facilitate the release of lipopolysaccharides (LPS) into the cytoplasm [94]. LPS can directly interact with murine caspase-11 or human caspase-4/5 and activate NLRP3 as a consequence of K+ efflux induced by GSDMD pores in the cell membrane or after sensing DAMPs released by pyroptotic cells, suggesting a functional crosstalk between the canonical and non-canonical pathways [95].

On the other hand, GSDMD pore formation has been found responsible for IL-1β release in the absence of pyroptotic cell death [96]. Likewise, calcium influx through GSDMD pores can act as a signal to induce membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged plasma membrane areas, inducing cell survival mechanisms beyond pyroptosis [97]. Moreover, IL-1β release upon activation of caspase-1 can be independent of GSDMD membrane permeabilization [98]. The different mechanisms involved in the activation of the NLRP3 inflammasome is a topic of active investigation and thus, in addition to the mechanisms described above, alternative molecular mechanisms have also been unveiled recently. Because of space concerns, we only reviewed here the more established mechanisms, but we refer the reader to [99][100][101] for a more detailed description of these novel mechanisms.

This entry is adapted from the peer-reviewed paper 10.3390/ijms22031064

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