Antagonistic Peptides That Specifically Bind to the First and Second Extracellular Loops of CCR5 and Anti-IL-23p19 Antibody Reduce Airway Inflammation by Suppressing the IL-23/Th17 Signaling Pathway

Published on Apr 28, 2020in Mediators of Inflammation3.758
· DOI :10.1155/2020/1719467
Yingli Zhang2
Estimated H-index: 2
(SYSU: Sun Yat-sen University),
Rongrong Liang1
Estimated H-index: 1
(SYSU: Sun Yat-sen University)
+ 3 AuthorsYingqiang Zhong2
Estimated H-index: 2
(SYSU: Sun Yat-sen University)
Sources
Abstract
Asthma is a heterogeneous chronic inflammatory disorder of the airways with a complex etiology, which involves a variety of cells and cellular components. Therefore, the aim of the study was to investigate the effects and mechanisms of antagonistic peptides that specifically bind to the first and second extracellular loops of CCR5 (GH and HY peptides, respectively) and anti-interleukin-23 subunit p19 (anti-IL-23p19) in the airway and thereby mediate inflammation and the IL-23/T helper 17 (Th17) cell pathway in asthmatic mice. An experimental asthma model using BALB/c mice was induced by ovalbumin (OVA) and treated with peptides that are antagonistic to CCR5 or with anti-IL-23p19. The extents of the asthmatic inflammation and mucus production were assessed. In addition, bronchoalveolar lavage fluid (BALF) was collected, the cells were counted, and the IL-4 level was detected by ELISA. The IL-23/Th17 pathway-related protein and mRNA levels in the lung tissues were measured, and the positive production rates of Th17 cells in the thymus, spleen, and peripheral blood were detected. The groups treated with one of the two peptides and/or anti-IL-23p19 showed significant reductions in allergic inflammation and mucus secretion; decreased expression levels of IL-23p19, IL-23R, IL-17A and lactoferrin (LTF); and reduced proportions of Th17 cells in the thymus, spleen, and peripheral blood. Specifically, among the four treatment groups, the anti-IL-23p19 with HY peptide group exhibited the lowest positive production rate of Th17 cells. Our data also showed a significant and positive correlation between CCR5 and IL-23p19 protein expression. These findings suggest that the administration of peptides antagonistic to CCR5 and/or anti-IL-23p19 can reduce airway inflammation in asthmatic mice, most likely through inhibition of the IL-23/Th17 signaling pathway, and the HY peptide can alleviate inflammation not only through the IL-23/Th17 pathway but also through other mechanisms that result in the regulation of inflammation.
📖 Papers frequently viewed together
15 Citations
103 Citations
20162.74PLOS ONE
6 Authors (Chao Wang, ..., Wei Xiao)
12 Citations
References33
Newest
#1Mark Lebwohl (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 112
3 CitationsSource
#1Joel Henrique Ellwanger (UFRGS: Universidade Federal do Rio Grande do Sul)H-Index: 12
#2José Artur Bogo Chies (UFRGS: Universidade Federal do Rio Grande do Sul)H-Index: 28
Abstract The human Tick-borne encephalitis virus (TBEV) infection is a complex event encompassing factors derived from the virus itself, the vectors, the final host, and the environment as well. Classically, genetic traits stand out among the human factors that modify the susceptibility and progression of infectious diseases. However, and although this is a changing scenario, studies evaluating the genetic factors that affect the susceptibility specifically to TBEV infection and TBEV-related dis...
8 CitationsSource
#1Yanchun Li (JLU: Jilin University)H-Index: 1
#2Xiuhua Yu (JLU: Jilin University)H-Index: 1
Last. Shucheng Hua (JLU: Jilin University)H-Index: 1
view all 4 authors...
Abstract Interleukin-23 (IL-23) is a cytokine that is composed of the subunits p19 and p40, while its receptor (IL-23R) consists of two subunits, that is, IL-23Rα and IL-12Rβ1. The interaction between IL-23 and IL-23R is necessary for exerting cardinal biological effects upon certain cell types, including promotion of memory T cell proliferation and Th17 cell-mediated IL-17 secretion. Accordingly, dendritic cells (DCs) are one of the main sources for IL-23 secretion. Interestingly, IL-23R is als...
9 CitationsSource
#1Uni Wong (UMB: University of Maryland, Baltimore)H-Index: 3
#2Raymond K. Cross (UMB: University of Maryland, Baltimore)H-Index: 29
ABSTRACTIntroduction: Blockade of interleukin (IL)-12 and IL-23 is a novel therapeutic target for inflammatory bowel disease (IBD). The monoclonal antibody targeting the shared p40 subunit of IL-12...
17 CitationsSource
#1Sheikh F. Ahmad (KSU: King Saud University)H-Index: 26
#2Mushtaq A. Ansari (KSU: King Saud University)H-Index: 24
Last. Sabry M. Attia (KSU: King Saud University)H-Index: 31
view all 9 authors...
Abstract Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviors. BTBR T+ Itpr3tf/J (BTBR) mice, a preclinical autistic model featuring ASD symptoms as defined by social relations, was used in this study. We evaluated the potentially protective effect of D -Ala-peptide T-amide (DAPTA), a selective C-C chemokine receptor 5 (CCR5) antagonist, in BTBR mice. CCR5 is considered a potential thera...
4 CitationsSource
#2Herbert TilgH-Index: 96
Last. Tim Raine (Cambridge University Hospitals NHS Foundation Trust)H-Index: 27
view all 3 authors...
IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn’s disease, including in Europe, the USA, Canada and Japan, whilst agents ta...
137 CitationsSource
#1Anne Brelot (French Institute of Health and Medical Research)H-Index: 18
#2Lisa A. Chakrabarti (French Institute of Health and Medical Research)H-Index: 27
Abstract The chemokine receptor CCR5 has been the focus of intensive studies since its role as a coreceptor for HIV entry was discovered in 1996. These studies lead to the development of small molecular drugs targeting CCR5, with maraviroc becoming in 2007 the first clinically approved chemokine receptor inhibitor. More recently, the apparent HIV cure in a patient transplanted with hematopoietic stem cells devoid of functional CCR5 rekindled the interest for inactivating CCR5 through gene therap...
36 CitationsSource
#1Bradley E. ChippsH-Index: 39
#2Tmirah HaselkornH-Index: 25
Last. Robert S. Zeiger (KP: Kaiser Permanente)H-Index: 95
view all 9 authors...
Background The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR I) study demonstrated high morbidity in patients with severe or difficult-to-treat asthma despite standard-of-care treatment. Objective We sought to determine the long-term natural history of disease and outcomes in patients in TENOR I after more than a decade. Methods TENOR I was a multicenter observational study (2001-2004) of 4756 patients with severe or difficult-to-treat asthma. TENOR II was a ...
42 CitationsSource
#1Fabio Luigi Massimo Ricciardolo (UNITO: University of Turin)H-Index: 36
#2Valentina Sorbello (UNITO: University of Turin)H-Index: 11
Last. Giorgio CiprandiH-Index: 69
view all 16 authors...
Background Severe asthma might be associated with overexpression of T h 17 cytokines, which induce neutrophil recruitment via neutrophil-mobilizing cytokines in airways. Objective To study IL-17–related cytokines in nasal/bronchial biopsies from controls and mild asthmatics (MAs) to severe asthmatics (SAs) in relation to exacerbation rate. Methods Inflammatory cells and IL-17A + , IL-17F + , IL-21 + , IL-22 + , and IL-23 + cells were examined by immunohistochemistry in cryostat sections of bronc...
68 CitationsSource
#1Marta Arimont (VU: VU University Amsterdam)H-Index: 7
#2Shan-Liang Sun (VU: VU University Amsterdam)H-Index: 3
Last. Chris de Graaf (VU: VU University Amsterdam)H-Index: 37
view all 6 authors...
This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine ...
56 CitationsSource
Cited By1
Newest
Purpose The mechanisms of CC chemokine receptor 5 (CCR5) in the process of autophagy remain unknown. In this study, we examined the role of HY peptide, which is an antagonistic peptide specifically binding the second extracellular loop of CCR5, in the expression of autophagy genes and β-arrestin 2 in lung tissues of asthmatic mice. Methods Experimental asthmatic mice were treated with HY peptide and dexamethasone sodium phosphate (Dex). Airway inflammation, autophagy-related genes, autophagic va...
1 CitationsSource