Inflammasomes: a novel therapeutic target in pulmonary hypertension?

Abstract

Pulmonary hypertension (PH) is a rare, progressive pulmonary vasculopathy characterized by increased mean pulmonary arterial pressure, pulmonary vascular remodelling and right ventricular failure. Current treatments are not curative, and new therapeutic strategies are urgently required. Clinical and preclinical evidence has established that inflammation plays a key role in PH pathogenesis, and recently, inflammasomes have been suggested to be central to this process. Inflammasomes are important regulators of inflammation, releasing the pro-inflammatory cytokines IL-1β and IL-18 in response to exogenous pathogen- and endogenous damage-associated molecular patterns. These cytokines are elevated in PH patients, but whether this is a consequence of inflammasome activation remains to be determined. This review will briefly summarize current PH therapies and their pitfalls, introduce inflammasomes and the mechanisms by which they promote inflammation and, finally, highlight the preclinical and clinical evidence for the potential involvement of inflammasomes in PH pathobiology and how they may be targeted therapeutically.

Transcriptomic analysis identifies Toll‐like and Nod‐like pathways and necroptosis in pulmonary arterial hypertension

“…The expression of IL‐1β, IL‐18, GSDMD and NLRP3 was elevated in NLR pathway, which was consistent with previously reported activation of NLRP3 inflammasome in PAH 20 . Lysosomal destabilization and CTSB release were capable of activating NLRP3 inflammasome following DAMP phagocytosis 40 .…”

“…Upon inflammasomes assembly and subsequent caspase‐1 activation, their effector mechanisms were then triggered, including release of activated IL‐1β and IL‐18 and initiation of gasdermin D (GSDMD)–mediated pyroptosis 19 . In addition to showing up‐regulation of previously reported inflammasome components and their effector molecules including NLRP3, ASC, IL‐1β and IL‐18, 20 further analysis of NLR signalling pathways using Pathview and Morpheus also showed less well‐characterized genes, such as elevated GSDMD, CTSB, p22phox and TRX1 (TXN1), and reduced AIM2, p202 and TXNIP in MCT‐induced PAH (Figure ; Figure 4C).…”

Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

“…The maturation of IL‐18 and IL‐1b in immune cells relies on the activation of inflammasomes, which in turn are activated by molecules originated from infectious micro‐organisms. Moreover, the activation of inflammasomes also activates caspase‐1 to convert pro‐IL‐18 and pro‐IL‐1b into their mature forms . It was reported that the reduction in inflammasome activation could significantly decrease the level of inflammatory responses in neurons as a result of decreased caspase‐1 activity and reduced production of IL‐1 .…”

“…In fact, it has been found that the reactive oxygen species (ROS) increased the activation of NLRP3 inflammasomes, which act as an essential mediator promoting the release of interleukin-18 (IL-18) and IL-1b. 15,16 It was reported that the reduction in inflammasome activation could significantly decrease the level of inflammatory responses in neurons as a result of decreased caspase-1 activity and reduced production of IL-1. 14 The maturation of IL-18 and IL-1b in immune cells relies on the activation of inflammasomes, which in turn are activated by molecules originated from infectious micro-organisms.…”

Emerging Role of the Inflammasome and Pyroptosis in Hypertension

“…The involvement of the NLRP3 inflammasome in human pulmonary hypertension is also a topic of active investigation, as reviewed by Scott et al [ 108 ], although research in this area is still in the early stages. In the pulmonary disease setting, expression of components of the inflammasome has been described in macrophages [ 109 ], endothelial cells [ 110 , 111 ], and lung epithelial cells [ 112 ].…”