The cathelicidin protein CRAMP is a potential atherosclerosis self-antigen in ApoE(-/-) mice

Mihailovic, Peter M.; Lio, Wai Man; Yano, Juliana; Zhao, Xiaoning; Zhou, Jianchang; Chyu, Kuang‐Yuh; Shah, Prediman K.; Cercek, Bojan; Dimayuga, Paul C.

doi:10.1371/journal.pone.0187432

Cited by 28 publications

(30 citation statements)

References 51 publications

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“…Peptides selected for screening as potential self-antigens were resuspended at a concentration of 20 µg/ml in RPMI 1,640 medium supplemented with 10% FBS and antibiotic/antimycotic (11,15). Splenocytes from 13 week-old mice of both sexes fed either normal chow or high fat diet were collected and subjected to RBC lysis.…”

Section: Peptide Screeningmentioning

confidence: 99%

“…Intracellular staining was performed using fixation and permeabilization steps. Another aliquot was incubated with a specific peptide for 24 h to profile Central Memory and Effector Memory T cells (11,15). See Table S1 for specific antibodies.…”

Section: Peptide Screeningmentioning

confidence: 99%

“…Mice fed normal chow were grouped into 1 of 3 immunization studies according to the appropriate sex: immunization of both sexes with a peptide common to both sexes, immunization of females with a female-unique peptide, or immunization of males with a male-unique peptide. Immunization was performed using subcutaneous injection of 20 µg of peptide formulated in Adjuvant consisting of Adju-Phos (Brenntag; 12.5 µl of a 2% solution) and 10 µg MPLA (MPLA-SM VacciGrade, InvivoGen) in a volume of 200 µl (11). Control was injection with Adjuvant alone.…”

Section: Immunizationmentioning

confidence: 99%

“…Control was injection with Adjuvant alone. Immunizations were performed at 7, 10, and 12 weeks of age (11,22). Mice were fed high fat diet at 13 weeks of age until euthanasia at 25 weeks of age.…”

Section: Immunizationmentioning

confidence: 99%

“…This would be inclusive of various HLA types since an antigen is not necessarily limited to a single HLA (9). Assuming that there are antigens common among CAD patients, some of these are potentially self-peptides given the chronic nature of CAD (10)(11)(12). Self-peptides are presented by class-I HLA as part of normal cellular homeostasis and is involved in immune surveillance (13).…”

Section: Introductionmentioning

confidence: 99%

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Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics

et al. 2020

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A significant body of work implicates the adaptive immune response in atherosclerosis, the main underlying cause of coronary artery disease (CAD), yet specific antigens involved remain to be fully identified. The pathobiology of CAD is influenced by sex with many factors that may be involved in the underlying mechanisms. Given the reported sexual dimorphic nature of immune-inflammatory responses, we investigated the influence of sex on potential CAD self-antigens from acute coronary syndrome (ACS) patients using immune-precipitation of soluble HLA Class-I/peptide complexes and mass spectrometry. Relevance of identified self-antigens to atherosclerosis, the major underlying cause of CAD, was tested in the apoE-/-atherosclerotic mouse model. Soluble HLA Class-I complexes from ACS patients and self-reported controls were immune-precipitated and subjected to elution, denaturation and size-exclusion to obtain HLA-bound peptides. Peptides were then subjected to mass spectrometry and patient-unique self-peptides were grouped as common to both female and male, or unique to either sex. Three peptides common to both female and male patients (COL6A1, CDSN, and SAA2), and 2 peptides each unique to female (COL1A1 and COL5A2) or male (SAA1 and KRT 9) patients were selected and mouse homologs of the peptides were screened for self-reactive immune responses in apoE-/-mice. The screening step revealed potential sex-influenced immune responses which was associated with differential immune profiles. Based on the frequency in patient plasma, COL6A1, COL5A2, and KRT 9 peptides were then tested in immunization studies. Neither COL5A2 nor KRT 9 peptide immunization resulted in significant effects on atherosclerosis compared to controls. On the other hand, female mice immunized with COL6A1 peptide had significantly reduced atherosclerosis whereas male mice had significantly increased atherosclerosis, associated with differential immune profiles. Our study identified potential self-antigens involved in atherosclerosis using the immune peptidome of CAD patients. Altering self-reactive immune responses to COL6A1 in apoE-/-mice resulted in differential effects on atherosclerosis burden with sex as a determinant of outcome.

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Section: Peptide Screeningmentioning

confidence: 99%

Section: Peptide Screeningmentioning

confidence: 99%

Section: Immunizationmentioning

confidence: 99%

Section: Immunizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics

et al. 2020

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Downregulation of G3BP2 reduces atherosclerotic lesions in ApoE mice

Safitri

Zhang

et al. 2020

Atherosclerosis

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IL-7R blockade reduces post-myocardial infarction-induced atherosclerotic plaque inflammation in ApoE−/- mice

Mihailovic

Lio

Yano

et al. 2019

Biochemistry and Biophysics Reports

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Modulating inflammation by targeting IL-1β reduces recurrent athero-thrombotic cardiovascular events without lipid lowering. This presents an opportunity to explore other pathways associated with the IL-1β signaling cascade to modulate the inflammatory response post-myocardial infarction (MI). IL-7 is a mediator of the inflammatory pathway involved in monocyte trafficking into atherosclerotic plaques and levels of IL-7 have been shown to be elevated in patients with acute MI. Recurrent athero-thrombotic events are believed to be mediated in part by index MI-induced exacerbation of inflammation in atherosclerotic plaques. The objective of the study was to assess the feasibility of IL-7R blockade to modulate atherosclerotic plaque inflammation following acute MI in ApoE −/- mice. Mice were fed Western diet for 12 weeks and then subjected to coronary occlusion to induce an acute MI. IL-7 expression was determined using qRT-PCR and immuno-staining, and IL-7R was assessed using flow cytometry. Plaque inflammation was evaluated using immunohistochemistry. IL-7R blockade was accomplished with monoclonal antibody to IL-7R. IL-7 mRNA expression was significantly increased in the cardiac tissue of mice subjected to MI but not in controls. IL-7 staining was observed in the coronary artery. Plaque macrophage and lipid content were significantly increased after MI. IL-7R antibody treatment but not control IgG significantly reduced macrophage and lipid content in atherosclerotic plaques. The results show that IL-7R antibody treatment reduces monocyte/macrophage and lipid content in the atherosclerotic plaque following MI suggesting a potential new target to mitigate increased plaque inflammation post-MI.

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The cathelicidin protein CRAMP is a potential atherosclerosis self-antigen in ApoE(-/-) mice

Cited by 28 publications

References 51 publications

Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics

Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics

Downregulation of G3BP2 reduces atherosclerotic lesions in ApoE mice

IL-7R blockade reduces post-myocardial infarction-induced atherosclerotic plaque inflammation in ApoE−/- mice

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