NLRP3 Inflammasome and MIF as therapeutic target in PAH

NLRP3 Inflammasome and MIF as therapeutic target in PAH

The role of NLRP3 Inflammasome in pulmonary hypertension supports the long recognized presence and role of specific cytokines, particularly IL-1b. and IL-18, but also enzymes as caspase-1 in non-clinical models, as well as in patients suffering from PAH (Mariathasan, 2006; Martinon, 2006, Hake, 2008).

This particular inflammatory pattern supports the role of NLRP3 inflammasomes as evidence that NLRP3-dependent activation of inflammasomes by endogenous danger signals (PAMPs, DAMPs) is associated with endothelial dysfunction and a particular form of cell death called pyroptosis (Maltez, 2015), common to the pathogenesis of several cardio-vascular conditions.

Targeting NLRP3 Inflammasome, and more specifically its NLRP3 component should therefore prove a more valid approach than single cytokine inhibition (with anti-IL1, or anti-IL6 therapies), caspase-1 inhibition, or by a more global immunomodulation (Scott, 2019). MFC-1040 is a Macrophage Inhibitory Factor (MIF)-neutralizing small molecule discovered by INSERM (Humbert et al.). Neutralized intracellular MIF reduces NLRP3 Inflammasome activation (Harris et al. Nature Comms 2020 ), while neutralizing circulating MIF reduces CD74 activation known to decrease in turn cell survival and proliferation, and to elicit the release of pro-inflammatory cytokines. Inhibiting circulating MIF may also reduce CXCR2 and 4 activation, thereby halting the recruitment of macrophages to inflamed tissue, and further reducing the pro-inflammatory effects of pyroptosis. In other words, combining a more direct and specific inhibition of NLRP3 Inflammasome activation with an inhibition of other MIF-related pro-inflammatory processes offer a novel disease-modifying option in the treatment of PAH and potentially many other inflammatory diseases.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that is elevated in patient plasma in many inflammatory diseases (Drug Discovery Today 2019, 24, 428-439) where NLRP3 inflammasomes are also involved. It is produced by a variety of immune cells, including macrophages and lymphocytes, as well as endothelial and epithelial cells under certain conditions. MIF occupies an upstream position in the inflammatory cascade, higher than TNF-alpha and IL-6, and is associated with glucocorticoid resistance.

MIF and its cell surface receptor CD74 were found upregulated in patients with PAH, and are key players at the crossroad of inflammation, cancer-like phenotype and endothelial dysfunction in the pathogenesis of PAH. It has been demonstrated that over-expression of the MIF/CD74 axis induces pro-inflammatory phenotype of human pulmonary endothelial cells (P-ECs). Those P-ECs release specific adhesion molecules (i.e. ICAM-1, VCAM-1, and E-selectin), facilitating the adhesion and recruitment of inflammatory cells to the pulmonary vascular wall (Am. J. Respir. Crit. Care Med. 2015, 192, 983-997).