LL-37 treatment on human peripheral blood mononuclear cells modulates immune response and promotes regulatory T-cells generation

Sternadt, Dominique; Silva-Carvalho, Amandda Évelin; Lacerda, Mariella G.; Serejo, Teresa Raquel Tavares; Franco, Octávio Luiz; Pereira, Rinaldo Wellerson; Carvalho, Juliana Lott; Neves, Francisco A. R.; Saldanha-Araújo, Felipe

doi:10.1016/j.biopha.2018.10.014

Cited by 15 publications

(7 citation statements)

References 35 publications

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“…LL-37 was reported to decrease T cell proliferation in resting human PBMCs with increased cell viability without changes in CD4+FoxP3+ T reg cell percentage suggesting that in the steady-state, LL-37 treatment results in a degree of immune-modulation apparently independent of increased T regs ( 25 ). In the same report, T cells increased proliferation when co-activated with phytohaemagglutinin without affecting cell viability and with increased T reg cells.…”

Section: Discussionmentioning

confidence: 99%

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

et al. 2020

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The human cationic anti-microbial peptide LL-37 is a T cell self-antigen in patients with psoriasis, who have increased risk of cardiovascular events. However, the role of LL-37 as a T cell self-antigen in the context of atherosclerosis remains unclear. The objective of this study was to test for the presence of T cells reactive to LL-37 in patients with acute coronary syndrome (ACS). Furthermore, the role of T cells reactive to LL-37 in atherosclerosis was assessed using apoE−/− mice immunized with the LL-37 mouse ortholog, mCRAMP. Peripheral blood mononuclear cells (PBMCs) from patients with ACS were stimulated with LL-37. PBMCs from stable coronary artery disease (CAD) patients or self-reported subjects served as controls. T cell memory responses were analyzed with flow cytometry. Stimulation of PBMCs with LL-37 reduced CD8+ effector T cell responses in controls and patients with stable CAD but not in ACS and was associated with reduced programmed cell death protein 1 (PDCD1) mRNA expression. For the mouse studies, donor apoE−/− mice were immunized with mCRAMP or adjuvant as controls, then T cells were isolated and adoptively transferred into recipient apoE−/− mice fed a Western diet. Recipient mice were euthanized after 5 weeks. Whole aortas and hearts were collected for analysis of atherosclerotic plaques. Spleens were collected for flow cytometric and mRNA expression analysis. Adoptive transfer experiments in apoE−/− mice showed a 28% reduction in aortic plaque area in mCRAMP T cell recipient mice (P < 0.05). Fifty six percent of adjuvant T cell recipient mice showed calcification in atherosclerotic plaques, compared to none in the mCRAMP T cell recipient mice (Fisher’s exact test P = 0.003). Recipients of T cells from mice immunized with mCRAMP had increased IL-10 and IFN- γ expression in CD8+ T cells compared to controls. In conclusion, the persistence of CD8+ effector T cell response in PBMCs from patients with ACS stimulated with LL-37 suggests that LL-37-reactive T cells may be involved in the acute event. Furthermore, studies in apoE−/− mice suggest that T cells reactive to mCRAMP are functionally active in atherosclerosis and may be involved in modulating plaque calcification.

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Section: Discussionmentioning

confidence: 99%

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

et al. 2020

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“…The expression levels of the five genes were assessed using quantitative RT-PCR (qRT-PCR), which was conducted according to manufacturer's instructions using SYBR TM Green real-time PCR (qPCR) master mix (Applied Biosystems, USA). The previously designed reverse and forward primers flanking mRNA transcripts of FOXP3 , IFN-γ , TNF , IL-6 and COX- 2 were used ( Alexandre-Ramos et al, 2018 ; Daneshmand et al, 2016 ; Fu et al, 1999 ; Madec et al, 2009 ; Mencarelli et al, 2009 ). β-actin was used as a reference gene and as a control in the relative quantification method.…”

Section: Methodsmentioning

confidence: 99%

Upregulation of FOXP3 is associated with severity of hypoxia and poor outcomes in COVID-19 patients

et al. 2021

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The levels of messenger RNA (mRNA) transcription of FOXP3, IFN-γ, TNF, IL-6 and COX-2 from both COVID-19 infected and control subjects were evaluated using SYBR TM green real-time polymerase chain reaction (RT-PCR). Severe/critical cases showed significantly lower lymphocyte counts and higher neutrophil counts than the mild or moderate cases. There were significantly lower levels of mRNA expressions of IFN-γ, TNFα and FOXP3 in COVID-19 patients than in the control group. On the other hand, IL-6 and COX-2 expressions were significantly higher in patients suffering from severe disease. FOXP3 expressions were correlated with the severities of hypoxia and were excellent in predicting the disease severity. This was followed by the IL-6, COX-2 and TNFα expressions. FOXP3 expression was the only biomarker to show a significant correlation with patient mortality. It was concluded that SARS-CoV-2 infection is associated with the downregulation of FOXP3 and upregulations of IL-6 and COX-2 .

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“…Thus, LL-37 appears to act as a bridge between the innate and adaptive immune systems [53], while LL-37 not only produces an enhanced Th1 response but also produces an adjuvant that enhances the Th17 response in the oral mucosa, where mFPR2 on M cells interacts with LL-37-Ag and is recognized by APC near the M cell, mature to CD11c + CD70 + APC, which subsequently produces a Th17-biased environment by increasing IL-17, and leads to an increase in the formation of germinal centre (GC) B cells and GC; thus, LL-37 mediates an Ag-specific immune response through regulating the mucosal immune environment [79]. Interestingly, by assessing the role of LL-37 in peripheral blood mononuclear cells (PBMC), the researchers found that LL-37 also promotes the production of regulatory T cells, while LL-37 does not affect T cell activation; in the context of inflammation (PHA activation), peptides can induce resting T cell proliferation, significantly increasing Tregs production and decreasing proinflammatory factor expression (INF-γ, TNF-α) of PBMC; indicating that when the peptide plays its own anti-infective property, the control proinflammatory responses are always accompanied, in order to protect the body against severe inflammatory response [80]. These results show the two sidedness of antimicrobial peptides.…”

Section: T Cellsmentioning

confidence: 99%

Significance of LL-37 on Immunomodulation and Disease Outcome

Yang

Good

Mosaiab

et al. 2020

BioMed Research International

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LL-37, also called cathelicidin, is an important part of the human immune system, which can resist various pathogens. A plethora of experiments have demonstrated that it has the multifunctional effects of immune regulation, in addition to antimicrobial activity. Recently, there have been increasing interest in its immune function. It was found that LL-37 can have two distinct functions in different tissues and different microenvironments. Thus, it is necessary to investigate LL-37 immune functions from the two sides of the same coin. On the one side, LL-37 promotes inflammation and immune response and exerts its anti-infective and antitumor effects; on the other side, it has the ability to inhibit inflammation and promote carcinogenesis. This review presents a brief summary of its expression, structure, and immunomodulatory effects as well as brief discussions on the role of this small peptide as a key factor in the development and treatment of various inflammation-related diseases and cancers.

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LL-37 treatment on human peripheral blood mononuclear cells modulates immune response and promotes regulatory T-cells generation

Cited by 15 publications

References 35 publications

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

Upregulation of FOXP3 is associated with severity of hypoxia and poor outcomes in COVID-19 patients

Significance of LL-37 on Immunomodulation and Disease Outcome

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