Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

Abstract

Calcific aortic valve disease (CAVD) is common in people over the age of 65. Progressive valvular calcification is a characteristic of CAVD and due to chronic inflammation in aortic valve interstitial cells (AVICs) resulting in CAVD progression. IL-38 is a naturally occurring anti-inflammatory cytokine; here, we report lower levels of endogenous IL-38 in AVICs isolated from patients’ CAVD valves compared to AVICs from non-CAVD valves. Recombinant IL-38 suppressed spontaneous inflammatory activity and calcium deposition in cultured AVICs. In mice, knockdown of IL-38 enhanced the production of inflammatory mediators in murine AVICs exposed to the proinflammatory stimulant matrilin-2. We also observed that in cultured AVICs matrilin-2 stimulation activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome with procaspase-1 cleavage into active caspase-1. The addition of IL-38 to matrilin-2–treated AVICs suppressed caspase-1 activation and reduced the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, runt-related transcription factor 2, and alkaline phosphatase. Aged IL-38–deficient mice fed a high-fat diet exhibited aortic valve lesions compared to aged wild-type mice fed the same diet. The interleukin-1 receptor 9 (IL-1R9) is the putative receptor mediating the anti-inflammatory properties of IL-38; we observed that IL-1R9–deficient mice exhibited spontaneous aortic valve thickening and greater calcium deposition in AVICs compared to wild-type mice. These data demonstrate that IL-38 suppresses spontaneous and stimulated osteogenic activity in aortic valve via inhibition of the NLRP3 inflammasome and caspase-1. The findings of this study suggest that IL-38 has therapeutic potential for prevention of CAVD progression.

The emerging role of IL‐38 in diseases: A comprehensive review

“…Hence, IL‐38 is a potential biomarker in acute myocardial infarction patients. The et al 46 found that IL‐38 inhibited osteogenic activity in the aortic valve by inhibiting the NLRP3 inflammasome and caspase‐1, indicating that IL‐38 had the potential to prevent aortic valve calcification. It has been shown that IL‐38 is an independently factor of stroke and death in patients with atrial fibrillation 47,48 .…”

IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion

“…IL-38 is an anti-inflammatory cytokine that can protect the organism challenged with highly inflammatory triggers, as recently observed in dextran sodium sulfate-colitis or aortic calcification models (6,7). We sought to confirm whether IL-38 is expressed in the mouse intestine (8) and if the IL-38 protein is expressed in the small intestine at the level of the stem cell crypts.…”

“…As demonstrated by Van de Veerdonk and collaborators, IL-38 has biological effects in immune cells that resembles IL-36Ra functions, downregulating the levels of IL-22, IL-17, and IFNγ in Candida-stimulated Th17 cells (5). A recent study by The and collaborators also demonstrated that IL-38 dampens aortic valve calcification, probably dependent on IL-1R9 (encoded by Il1rapl1 gene), inhibiting NLR family pyrin domain containing 3 (NLRP3) and IL-1β maturation (6). Moreover, Il1f10 deficient mice exhibit higher levels of inflammation when exposed to DSS treatment compared to wild type mice and express higher levels of NLRP3 and caspase-1 (7).…”

Emerging functions and therapeutic targets of IL‐38 in central nervous system diseases

“…The novel cytokine IL-38 exerts anti-inflammatory effects in most diseases, including AD. [79][80][81] Yahya et al found that the expression level of IL-38 in the serum of newly diagnosed AD patients was pronouncedly increased compared with that in the serum of healthy control subjects. Notably, serum IL-38 expression levels were further increased in elderly male AD patients treated with anti-inflammatory drugs (memantine), while this phenomenon was not observed in elderly women, indicating that IL-38 mediates the anti-inflammatory protective function of memantine in AD and is sex-dependent.…”