IL-38 Gene Deletion Worsens Murine Colitis

Graaf, Dennis M. de; Wang, Ruth X.; Amo-Aparicio, Jesús; Lee, J. Scott; Dowdell, Alexander S.; Tengesdal, Isak W.; Marchetti, Carlo; Colgan, Sean P.; Joosten, Leo A. B.; Dinarello, Charles A.

doi:10.3389/fimmu.2022.840719

Cited by 12 publications

(16 citation statements)

References 48 publications

(67 reference statements)

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“…Recent studies have reported that IL-38 inhibits NLRP3 inflammasome activation induced by lipopolysaccharide (LPS) in macrophages and IL-1β production in chondrocytes ( 44 , 45 ). In addition, IL-38– deficient mice subjected to dextran sulfate sodium colitis exhibit increased colonic Nlrp3 mRNA and protein expression, as well as caspase-1 processing in comparison to WT mice ( 46 ). In this study, we observed that matrilin-2 up-regulates NLRP3 inflammasome levels and caspase-1 cleavage in AVICs.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

The

Graaf

Zhai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 99%

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

The

Graaf

Zhai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…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).…”

Section: Introductionmentioning

confidence: 95%

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

Dinarello

May

Amo-Aparicio

et al. 2023

Preprint

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The IL-1 Family member IL-38 has been characterized as an anti-inflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL 38 in the small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL 38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL 38 deficient mice develop more slowly. This reduction in size is likely due to downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, Olfm4) expression compared with wild type organoids. IL-38 binding to IL-1R6 is postulated to recruit the co-receptor IL-1R9. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL 1R9 deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL 38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL 38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild type mice, IL-38 stimulation induced low concentrations of IL-1β which contribute to organoid growth. However, high concentrations of IL 1beta have detrimental effects on the cultures that were prevented by treatment with recombinant IL 38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an anti-inflammatory molecule in the SI, maintaining homeostasis.

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“…Evidence for the protective role of IL-38 in intestinal mucosal immunity is demonstrated by substantially more severe clinical presentations (both systemic and local) and histopathological damage in intestinal mucosa from the IL-38 deficient mice, accompanied with more pro-inflammatory cytokines/chemokines ( 31 ) in response to dextran sulfate sodium (DSS) challenge, compared to wildtype mice. On the other hand, exogenous IL-38 ameliorates DSS induced colitis with substantially reduced systemic and local pro-inflammatory mediators ( 32 ).…”

Section: Il-38 In Intestinal Mucosal Immunitymentioning

confidence: 99%

“…However, there is substantial upregulation of IL-38 in the intestinal mucosa from IBD patients ( 11 , 35 ) at both molecular and cellular levels, correlating well with the disease severity, although IL-38 is classified as anti-inflammatory cytokine. The discrepancy of the possible role of IL-38 in colitis between experimentally induced colitis in animal models ( 31 , 32 ) and human IBD ( 11 , 35 ) may have several causes. First, disease progression in experimentally induced colitis is only 1-3 weeks in animals with acute progression; whereas the course of human IBD is usually is over 10 years.…”

Section: Il-38 In Intestinal Mucosal Immunitymentioning

confidence: 99%

“…This explanation is supported by other studies showing that chronic uncontrolled inflammation promotes malignancy in the colon, due to persistent damage of epithelial cells ( 37 ), consistent with the report of a close correlation between inflammatory bowel disease and the development of CRC ( 38 ). Moreover, down-regulated colonic IL-38 suppresses anti-inflammatory function and consequently promotes inflammation in the microenvironment, a phenomenon demonstrated in IL-38 gene knockout mice, showing substantially up-regulated pro-inflammatory mediators in the colon ( 31 ). The protective role of IL-38 is further supported by studies showing that IL-38 provides protection against gestational diabetes mellitus-induced inflammation within the placenta ( 39 ).…”

Section: Il-38 In Colorectal Cancermentioning

confidence: 99%

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The role of IL-38 in intestinal diseases - its potential as a therapeutic target

Wang

et al. 2022

Front. Immunol.

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IL-38, an anti-inflammatory cytokine, is a key regulator of homeostasis in host immunity. Intestinal immunity plays a critical role in defence against pathogenic invasion, as it is the largest surface organ and the most common entry point for micro-organisms. Dysregulated IL-38 activity is observed in several autoimmune diseases including systemic lupus erythematosus and atherosclerosis. The protective role of IL-38 is well illustrated in experimental colitis models, showing significantly worse colitis in IL-38 deficient mice, compared to wildtype mice. Moreover, exogenous IL-38 has been shown to ameliorate experimental colitis. Surprisingly, upregulated IL-38 is detected in inflamed tissue from inflammatory bowel disease patients, consistent with increased circulating cytokine levels, demonstrating the complex nature of host immunity in vivo. However, colonic IL-38 is significantly reduced in malignant tissues from patients with colorectal cancer (CRC), compared to adjacent non-cancerous tissue. Additionally, IL-38 expression in CRC correlates with 5-year survival, tumour size and differentiation, suggesting IL-38 plays a protective role during the development of CRC. IL-38 is also an independent biomarker for the prognosis of CRC, offering useful information in the management of CRC. Taken together, these data demonstrate the role of IL-38 in the maintenance of normal intestinal mucosal homeostasis, but that dysregulation of IL-38 contributes to initiation of chronic inflammatory bowel disease (resulting from persistent local inflammation), and that IL-38 provides protection during the development of colorectal cancer. Such data provide useful information for the development of novel therapeutic targets in the management of intestinal diseases for more precise medicine.

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IL-38 Gene Deletion Worsens Murine Colitis

Cited by 12 publications

References 48 publications

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

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

The role of IL-38 in intestinal diseases - its potential as a therapeutic target

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