Interleukin-7 protects against bacterial respiratory infection by promoting IL-17A-producing innate T-cell response

Hassane, Maya; Jouan, Youenn; Creusat, Florent; Soulard, Daphnée; Boisseau, Chloé; Gonzalez, Loïc; Patin, Emmanuel C.; Heuzé-Vourc’h, Nathalie; Sirard, Jean‐Claude; Faveeuw, Christelle; Trottein, François; Si‐Tahar, Mustapha; Baranek, Thomas; Paget, Christophe

doi:10.1038/s41385-019-0212-y

Cited by 35 publications

(39 citation statements)

References 67 publications

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“…But besides IL-17A and IL-17F levels, levels of downstream cytokines IL-6 and IL-8 also did not decrease on the group level after ustekinumab treatment. A possible explanation for the lack of effect on IL-17A and F expression levels observed in our study could be that IL-17 can not only be produced in a IL-23-dependent fashion by Th17 cells, but also independent of IL-23 by innate like lymphocytes (28,29), and that these IL-23 independent sources are more important in psoriatic synovium than skin. Unfortunately, we were unable to perform functional studies for verification.…”

Section: Discussioncontrasting

confidence: 65%

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

et al. 2021

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Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear.Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients.Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR).Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis.Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.

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Section: Discussioncontrasting

confidence: 65%

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

et al. 2021

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“…Consistent with this concept, higher MAIT cell functionality correlates with protection from nasopharyngeal colonisation by S. pneumoniae in healthy individuals [52]. Moreover, there is evidence from animal models that administration of MR1-presented agonist adjuvanted with Toll-like receptor (TLR) ligands, or supplementation with IL-7, enhances MAIT cell numbers and antimicrobial effector function, and affords protection from subsequent bacterial challenges [19,20,72]. IL-7 administration in vivo boosts MAIT cell numbers in humans [73].…”

Section: Open Accessmentioning

confidence: 87%

Emerging Role for MAIT Cells in Control of Antimicrobial Resistance

Leeansyah

Boulouis

Kwa

et al. 2021

Trends in Microbiology

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Antimicrobial resistance is a serious threat to global public health as antibiotics are losing effectiveness due to rapid development of resistance. The human immune system facilitates control and clearance of resistant bacterial populations during the course of antimicrobial therapy. Here we review current knowledge of mucosa-associated invariant T (MAIT) cells, an arm of the immune system on the border between innate and adaptive, and their critical place in human antibacterial immunity. We propose that MAIT cells play important roles against antimicrobialresistant infections through their capacity to directly clear multidrug-resistant bacteria and overcome mechanisms of antimicrobial resistance. Finally, we discuss outstanding questions pertinent to the possible advancement of hostdirected therapy as an alternative intervention strategy for antimicrobial-resistant bacterial infections. Antimicrobial Resistance and Host Immunity HighlightsHost immunity is an important factor in clearing antibiotic-resistant bacterial infections that is often neglected. Understanding host immunity can provide novel insights for alternative intervention strategies against antimicrobial resistance.Mucosa-associated invariant T (MAIT) cells are key players in human antibacterial immunity. These highly abundant unconventional T cells recognise byproducts from bacterial vitamin B 2 biosynthesis, and mediate bacterial control through direct killing and orchestrating downstream immune responses.MAIT cells have the capacity to control drug-resistant bacteria and overcome resistance. This suggests that MAIT cells may participate in the clearance of bacteria that acquire resistance during antibiotic therapy and may provide protection against infections by resistant bacteria.Enhancing MAIT cell properties may be a viable prophylaxis and alternative treatment strategy in vulnerable populations.

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“…Additionally, IL-7 is involved in CD4 + and CD8 + memory T cell responses [ 43 ]. At mucosal barriers, IL-7 promotes IL-17A responses against respiratory bacterial infection [ 44 ] and aids in the elimination of activated lymphocytes in the inflamed mucosa [ 45 ]. Our data show that IN and i.m.…”

Section: Discussionmentioning

confidence: 99%

Vaccination Route Determines the Kinetics and Magnitude of Nasal Innate Immune Responses in Rainbow Trout (Oncorhynchus mykiss)

Dong

Tacchi

et al. 2020

Biology

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Many pathogens infect animal hosts via the nasal route. Thus, understanding how vaccination stimulates early nasal immune responses is critical for animal and human health. Vaccination is the most effective method to prevent disease outbreaks in farmed fish. Nasal vaccination induces strong innate and adaptive immune responses in rainbow trout and was shown to be highly effective against infectious hematopoietic necrosis (IHN). However, direct comparisons between intranasal, injection and immersion vaccination routes have not been conducted in any fish species. Moreover, whether injection or immersion routes induce nasal innate immune responses is unknown. The goal of this study is to compare the effects of three different vaccine delivery routes, including intranasal (IN), intramuscular (i.m.) injection and immersion (imm) routes on the trout nasal innate immune response. Expression analyses of 13 immune-related genes in trout nasopharynx-associated lymphoid tissue (NALT), detected significant changes in immune expression in all genes analyzed in response to the three vaccination routes. However, nasal vaccination induced the strongest and fastest changes in innate immune gene expression compared to the other two routes. Challenge experiments 7 days post-vaccination (dpv) show the highest survival rates in the IN- and imm-vaccinated groups. However, survival rates in the imm group were significantly lower than the IN- and i.m.-vaccinated groups 28 dpv. Our results confirm that nasal vaccination of rainbow trout with live attenuated IHNV is highly effective and that the protection conferred by immersion vaccination is transient. These results also demonstrate for the first time that immersion vaccines stimulate NALT immune responses in salmonids.

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Interleukin-7 protects against bacterial respiratory infection by promoting IL-17A-producing innate T-cell response

Cited by 35 publications

References 67 publications

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

Emerging Role for MAIT Cells in Control of Antimicrobial Resistance

Vaccination Route Determines the Kinetics and Magnitude of Nasal Innate Immune Responses in Rainbow Trout (Oncorhynchus mykiss)

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