Different CFTR modulator combinations downregulate inflammation differently in cystic fibrosis

Abstract

Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.

Airway Inflammation and Host Responses in the Era of CFTR Modulators

“…Along with the increased influx of neutrophils and other immune cells, impaired function of these cells, and aberrant pro-inflammatory pathways, the lungs of PWCF also exhibit an inability to resolve inflammation appropriately due to deficient or downregulated counter-inflammatory mechanisms. These include the reduced secretion of the anti-inflammatory cytokine IL-10 from CF macrophages [ 96 , 105 ], reduction of the immunomodulator nitric oxide (NO) [ 106 , 107 ], suppressed levels of the anti-neutrophilic molecule lipoxin A4 [ 108 ], and MMP-9 cleavage of surfactant protein D [ 109 , 110 ]. Additionally, the endogenous lipid mediator resolvin RvD1, which is a potent regulator or resolution, has reduced receptor expression in CF macrophages and epithelial cells, leading to sustained lung inflammation and uncleared infection [ 111 , 112 ].…”

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

“…Associations of these molecules, the first ones being currently prescribed in routine since the mid-2010s, restore chloride transport and normalizing sweat test results ( Lopes-Pacheco, 2019 ). Beside their main action on epithelial chloride transport and encouraging results on disease progression, their impact on inflammatory cytokine production are controversial and their long term immunomodulatory effects are still discussed ( Jarosz-Griffiths et al, 2020 ; Volkova et al, 2020 ). Indeed, the corrector VX809 does not produce an effect on proinflammatory cytokines production by macrophages exposed to P. aeruginosa while stimulating their phagocytosis activity.…”

“…One promising therapy recently emerged, with small molecule correctors of mutated CFTR, which improve CFTR function and trafficking to the plasma-membrane [for recent review, see ( Lopes-Pacheco, 2019 )]. However, these therapies are gene mutation specific and their long-term impact on airway inflammation is still controversial ( Jarosz-Griffiths et al, 2020 ; Volkova et al, 2020 ). To date there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients.…”

The Effects of Nano-Curcumin as A Nutritional Strategy on Clinical and Inflammatory Factors in Children with Cystic Fibrosis: A Protocol Study and Review Article

“…Ivacaftor and tezacaftor act as the potentiator through enabling the opening chloride channel, while lumacaftor acts as the corrector through increasing the tra cking of the CFTR proteins to the outer cell membrane (5,6). Although these drugs could reduce airway in ammation, they cannot eliminate it completely (7). On the other hand, these drugs affect speci c mutations and do not cover all patients with various mutations (7).…”

“…Although these drugs could reduce airway in ammation, they cannot eliminate it completely (7). On the other hand, these drugs affect speci c mutations and do not cover all patients with various mutations (7). Therefore, anti-in ammatory treatments are an inevitable therapy for CF patients.…”