Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Puccetti, Matteo; Pariano, Marilena; Renga, Giorgia; Santarelli, Ilaria; D’Onofrio, Fiorella; Bellet, Marina Maria; Stincardini, Claudia; Bartoli, Andréa; Costantini, Claudio; Romani, Luigina; Ricci, Maurizio; Giovagnoli, Stefano

doi:10.3390/cells10071601

Cited by 18 publications

(15 citation statements)

References 50 publications

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“…56 We have indeed shown that 3-IAld exhibited potent antimicrobial activity in vitro 57 and modulated the composition of airway and gut microbiota in Open access murine model of cystic fibrosis. 58 Alternatively, 3-IAld may affect the microbiota composition via the regulatory activity of IL-22 on the microbiota. 45 This mechanism has been recently reported for indole-3-carbinol that, by inducing IL-22 from ILC type 3, promoted the expansion of butyrateproducing bacteria, such as Roseburia spp.…”

Section: Discussionmentioning

confidence: 99%

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Renga

Nunzi

Pariano

et al. 2022

J Immunother Cancer

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BackgroundDespite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manageable side effects to existing ICIs would enhance and expand their therapeutic efficacy and application. Due to its proven role in cancer development and immune regulation, gut microbiome has gained increasing expectation as a potential armamentarium to optimize immunotherapy with ICI. However, much has to be learned to fully harness gut microbiome for clinical applicability. Here we have assessed whether microbial metabolites working at the interface between microbes and the host immune system may optimize ICI therapy.MethodsTo this purpose, we have tested indole-3-carboxaldehyde (3-IAld), a microbial tryptophan catabolite known to contribute to epithelial barrier function and immune homeostasis in the gut via the aryl hydrocarbon receptor (AhR), in different murine models of ICI-induced colitis. Epithelial barrier integrity, inflammation and changes in gut microbiome composition and function were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 and IL-22 knockout mice were used to investigate the mechanism of 3-IAld activity. The function of the microbiome changes induced by 3-IAld was evaluated on fecal microbiome transplantation (FMT). Finally, murine tumor models were used to assess the effect of 3-IAld treatment on the antitumor activity of ICI.ResultsOn administration to mice with ICI-induced colitis, 3-IAld protected mice from intestinal damage via a dual action on both the host and the microbes. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that FMT from 3-IAld-treated mice protected against ICI-induced colitis with the contribution of butyrate-producing bacteria. Importantly, while preventing intestinal damage, 3-IAld did not impair the antitumor activity of ICI.ConclusionsThis study provides a proof-of-concept demonstration that moving past bacterial phylogeny and focusing on bacterial metabolome may lead to a new class of discrete molecules, and that working at the interface between microbes and the host immune system may optimize ICI therapy.

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Section: Discussionmentioning

confidence: 99%

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Renga

Nunzi

Pariano

et al. 2022

J Immunother Cancer

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“…This may broaden the therapeutic potential of microbial metabolites such as 3-IAld, and demands for drug delivery platforms for targeted therapies of a variety of clinical settings. For 3-IAld, in particular, its therapeutic activity in mice with cystic fibrosis [ 50 ] likely predicts an effect on extrapulmonary manifestations observed in these patients [ 51 ], such as cholangiopathy, to which, in addition to the genetic mutation, abnormal intestinal permeability combined with diet-induced dysbiosis are known to contribute [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Indole-3-Carboxaldehyde Restores Gut Mucosal Integrity and Protects from Liver Fibrosis in Murine Sclerosing Cholangitis

D’Onofrio

Renga

Puccetti

et al. 2021

Cells

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Primary sclerosing cholangitis (PSC) is a long-term liver disease characterized by a progressive course of cholestasis with liver inflammation and fibrosis. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC. According to the “leaky gut” hypothesis, gut inflammation alters the permeability of the intestinal mucosa, with the translocation of gut-derived products that enter the enterohepatic circulation and cause hepatic inflammation. Thus, the administration of molecules that preserve epithelial barrier integrity would represent a promising therapeutic strategy. Indole-3-carboxaldehyde (3-IAld) is a microbial-derived product working at the interface between the host and the microbiota and is able to promote mucosal immune homeostasis in a variety of preclinical settings. Herein, by resorting to a murine model of PSC, we found that 3-IAld formulated for localized delivery in the gut alleviates hepatic inflammation and fibrosis by modulating the intestinal microbiota and activating the aryl hydrocarbon receptor-IL-22 axis to restore mucosal integrity. This study points to the therapeutic potential of 3-IAld in liver pathology.

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“…The effect of ivacaftor was investigated also on monocyte/macrophage by several studies that made use of modern proteomics and transcriptomics techniques. [ 125 , 126 , 127 , 128 ]. Hisert et al performed a proteomic analysis of the plasma membrane of monocytes from 12 patients with CFTR -G551D mutations before, 2, and 7 days after treatment with ivacaftor finding a marked increase in levels of proteins implicated in cell migration [ 125 ].…”

Section: Cftr Modulators and Their Impact On Phagocytesmentioning

confidence: 99%

“…An analogous investigation was subsequently performed by Pedrazzi et al, who analyzed the modifications in the proteomic profile related to restored CFTR activity in PBMCs isolated from CF subjects carrying residual function mutations eligible for Ivacaftor therapy after ex vivo treatment with this potentiator [ 126 ]. Authors reported a downregulation both of proteins involved in the leukocyte transendothelial migration, contrary to what was highlighted by Hisert and colleagues, and in the regulation of actin cytoskeleton pathways after ivacaftor treatment.…”

Section: Cftr Modulators and Their Impact On Phagocytesmentioning

confidence: 99%

Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

Meoli

Eickmeier

Pisi

et al. 2022

IJMS

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Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.

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Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Cited by 18 publications

References 50 publications

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Indole-3-Carboxaldehyde Restores Gut Mucosal Integrity and Protects from Liver Fibrosis in Murine Sclerosing Cholangitis

Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

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