Cathelicidin-deficient mice exhibit increased survival and upregulation of key inflammatory response genes following cecal ligation and puncture

Severino, Patrícia; Ariga, Suely Kubo; Barbeiro, Hermes Vieira; Lima, Thaís Martins de; Silva, Elisangela de Paula; Barbeiro, Denise Frediani; Machado, Marcel Cerqueira César; Nizet, Victor; Silva, Fabiano Pinheiro da

doi:10.1007/s00109-017-1555-z

Cited by 25 publications

(23 citation statements)

References 48 publications

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“…Nevertheless, contradictory evidence also exists in the literature. Severino et al reported that wild-type C57BL/6 mice succumbed more rapidly to CLP compared with cathelicidin-deficient mice [35]. The discrepancies between this report and our study might arise from the genetic backgrounds of mice (129/SVJ and C57BL/6, respectively).…”

Section: Discussioncontrasting

confidence: 93%

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Chan

Liang

et al. 2020

Crit Care

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Objectives: The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated.Design: To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp +/+ ) and knockout (Cnlp −/− ) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. Results: The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms.Conclusions: Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

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Section: Discussioncontrasting

confidence: 93%

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Chan

Liang

et al. 2020

Crit Care

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“…Endogenous mCRAMP production is induced by Clostridium difficile , but fails to protect the host from inflammatory damage, whereas adding exogenous LL-37 or mCRAMP reduces TNFα production induced by toxins [ 114 ]. However, in a polymicrobial sepsis model, mCRAMP knockout mice had increased survival compared to the wild-type [ 115 ].…”

Section: Biological Functions Of Cathelicidinsmentioning

confidence: 99%

Cathelicidins: Immunomodulatory Antimicrobials

et al. 2018

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Cathelicidins are host defense peptides with antimicrobial and immunomodulatory functions. These effector molecules of the innate immune system of many vertebrates are diverse in their amino acid sequence but share physicochemical characteristics like positive charge and amphipathicity. Besides being antimicrobial, cathelicidins have a wide variety in immunomodulatory functions, both boosting and inhibiting inflammation, directing chemotaxis, and effecting cell differentiation, primarily towards type 1 immune responses. In this review, we will examine the biology and various functions of cathelicidins, focusing on putting in vitro results in the context of in vivo situations. The pro-inflammatory and anti-inflammatory functions are highlighted, as well both direct and indirect effects on chemotaxis and cell differentiation. Additionally, we will discuss the potential and limitations of using cathelicidins as immunomodulatory or antimicrobial drugs.

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“…Cathelicidins have the ability to enhance or inhibit the immune response, depending on the disease and cellular context (Pinheiro da Silva& Machado, 2017). Indeed, while CRAMP is protective in the course of localized Streptococcus Group A infection(Nizet et al, 2001), we found that it is detrimental in sepsis induced by cecal ligation and puncture, by inhibiting the production and release of several inflammatory mediators, especially IL-1β, IL-6, and MCP-1(Severino et al, 2017).Defensins are small, cysteine-rich peptides classified in two major subgroups: α-and β-defensins, based on their amino acid sequences and patterns of disulfide bond connectivity (de Paula & Valente, 2018). Human β-defensins 1-4 are the best well-characterized.…”

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confidence: 73%

Antimicrobial peptides in the gut–brain axis: A straightforward review to unravel some missing links

Silva

Bruzaferro

Câmara

2020

J of Neuroscience Research

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The intestinal microbiome has become a topic of intense scientific research, especially in the last 20 years, due to the hypothesis that it could have a critical influence in health and disease. Dysbiosis was the term coined to define the imbalance in intestinal microorganisms' equilibrium. More recently, a new wave of progress is taking place in this field, due to the emergence of high throughput technologies and big data analyses (Tropini, Earle, Huang, & Sonnenburg, 2017). In this mini review, we highlight the central concepts that we believe crucial to understand microbial behavior in the gut, in the brain, and its interaction with the immune system with a focus on antimicrobial peptides (AMPs). A great part of our point of view rely on experiments performed not only by our research group, but also by prominent scientists in the field during the last decade. Finally, we provide some provocative ideas to serve as a bridge and to provide linearity to such a fragmented area. Variation in microbial localization and density has been described along the entire intestinal tract with important pathophysiological implications (Tropini et al., 2017). Indeed, a tight balance is necessary to maintain homeostasis and when deregulated, the microbiota can promote not only intestinal diseases, but also affect distant organs. Among them, much attention has been directed to the brain, since brain and gut communicate through a number of complex pathways that include the central and autonomic nervous system, the hypothalamus-pituitary axis, and the enteric nervous plexuses (Mukhtar, Nawaz, & Abid, 2019). The gut-brain axis interacts in a bidirectional manner. Intestinal diseases can influence the brain and vice versa. In some cases, individual taxa are associated with a disease, whereas in other diseases,

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Cathelicidin-deficient mice exhibit increased survival and upregulation of key inflammatory response genes following cecal ligation and puncture

Cited by 25 publications

References 48 publications

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Cathelicidins: Immunomodulatory Antimicrobials

Antimicrobial peptides in the gut–brain axis: A straightforward review to unravel some missing links

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