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. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

Figure 1

Inflammation in pulmonary hypertension. Proposed mechanisms by which inflammation contributes to PH pathogenesis. Recruitment of inflammatory cells such as macrophages, T and B lymphocytes, dendritic and mast cells leads to the release of pro‐inflammatory cytokines IL‐1β, IL‐2, IL‐6, IL‐8, IL‐12, IL‐18 and TNF‐α, MCP‐1 and CXCL10. Platelet P‐selectin binds PSGL‐1 expressed on leukocytes to induce multicellular aggregation and trans‐endothelial migration. Here, inflammatory cells take up residence to form perivascular inflammatory infiltrates seen in the plexiform lesions of PH patients. This results in further cytokine release, pulmonary vascular remodelling, cell proliferation and thrombosis causing an ongoing exacerbation cycle.

Figure 2

Inflammasome isoforms and subunit compositions. The main inflammasome isoforms described to date include NLRP1, NLRP3, NLRC4, AIM2 and IFI16; the subunit composition differs depending on the variant. NLRP3, AIM2 and IFI16 inflammasomes require the adaptor molecule ASC for homotypic oligomerization. Conversely, NLRC4 contains its own CARD domain and can recruit pro‐caspase‐1 independently of ASC. NLRP1 contains both a CARD and PYD and can therefore either recruit caspase‐1 independently of ASC using its own CARD, or recruit caspase‐1 in an ASC‐dependent manner, similarly to the NLRP3, AIM2 and IFI16 inflammasomes. FIIND, function to find domain; HIN200, dsDNA binding domain.

Figure 3

NLRP3 inflammasome activation. Schematic representation of activators and effectors of the NLRP3 inflammasome. The NLRP3 inflammasome comprises the pattern recognition receptor, NLRP3, along with the adaptor molecule, ASC, and pro‐caspase‐1. NLRP3 inflammasome activation requires two steps. (1) Priming is induced by engagement of TLRs and pro‐inflammatory cytokine receptors on the cell surface by exogenous PAMPs (e.g. microbial components, silica crystals, asbestos fibres or pore‐forming toxins), endogenous DAMPs (e.g. ATP, microcrystals or ROS) or pro‐inflammatory cytokines such as TNF‐α; this results in NF‐κB‐mediated up‐regulation of NLRP3, ASC, pro‐caspase‐1, pro‐IL‐1β and pro‐IL‐18 gene expression. (2) Activation occurs when further DAMPs are detected by NLRP3. This leads to oligomerization of NLRP3 subunits and recruitment of ASC and pro‐caspase‐1. Pro‐caspase‐1 then undergoes auto‐cleavage into p10 and p20 subunits, which heterodimerize to form active caspase‐1. Caspase‐1 then processes pro‐IL‐1β and pro‐IL‐18 into their active, pro‐inflammatory cytokine forms IL‐1β and IL‐18.

Figure 4

Involvement of the NLRP3 inflammasome and potential sites of modulation in pulmonary hypertension. Numerous drugs are able to modulate NLRP3 inflammasome activity at various levels in PH; from activation to downstream cytokines. Priming is followed by assembly and activation of the NLRP3 inflammasome, resulting in subsequent pro‐inflammatory cytokine generation (Figure 3). The actions of these cytokines are thought to contribute to pulmonary vascular remodelling (Figure 1), which occurs alongside increased mPAP. These effects lead to RV compensatory hypertrophy and eventually RV decompensation, failure and death. Inhibitory drugs are in purple squares. IMD‐0354, selective NF‐κB inhibitor; A‐740003, P2X7 receptor inhibitor; Allopurinol/uricase, uric acid inhibitors; MnTE‐2‐PyP, SOD mimetic; MCC950, selective, low MW NLRP3 inflammasome activation inhibitor; VX‐765, caspase‐1 inhibitor; Anakinra, recombinant IL‐1 decoy receptor, IL1‐RA; Canakinumab, human monoclonal antibody targeting IL‐1β; r‐hIL‐18BP, recombinant IL‐18 decoy receptor, IL‐18BP; Tocilizumab, human monoclonal antibody targeting IL‐6 receptor (IL‐6R).