Clinical Implications of IL-32, IL-34 and IL-37 in Atherosclerosis: Speculative Role in Cardiovascular Manifestations of COVID-19

Law, Ching Chee; Puranik, Rajesh; Fan, Jingchun; Fei, Jian; Hambly, Brett D.; Bao, Shisan

doi:10.3389/fcvm.2021.630767

Cited by 24 publications

(20 citation statements)

References 117 publications

(149 reference statements)

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“…Dysregulated IL-37 has been reported in a number of auto-immune diseases, e.g., rheumatoid arthritis (11), psoriasis, Grave's disease and systemic lupus erythematous, and in ulcerative colitis and Crohn's disease (12), and in gestational diabetes mellitus (13), acting perhaps via inhibiting the expression and function of pro-inflammatory cytokines (11,12,14). In addition, it has been well-reviewed that IL-37 substantially reduces the development of atherosclerosis (15), which has been confirmed in an IL-37 transgenic animal model (16).…”

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confidence: 99%

The Role of IL-37 and IL-38 in Colorectal Cancer

Deng

Cui

et al. 2022

Front. Med.

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Colorectal cancer (CRC) is a major killer. Dysregulation of IL-37 and IL-38, both anti-inflammatory cytokines, is observed in auto-immune diseases. The precise regulatory mechanisms of IL-37/IL-38 during the development of CRC remains unclear, but chronic intestinal inflammation is involved in the carcinogenesis of CRC. Constitutive production of colonic IL-37 and IL-38 is substantially reduced in CRC, consistent with an inverse correlation with CRC differentiation. Reduced colonic IL-37 and IL-38 is relating to CRC invasion and distant metastasis, suggesting a protective role for IL-38 within the tumor micro-environment. IL-38 is reduced in right-sided CRC compared to left-sided CRC, which is in line with multiple risk factors for right-sided CRC, including the embryonic development of the colon, and genetic differences in CRC between these two sides. Finally, colonic IL-37 and tumor associated neutrophils (TAN) seem to be independent biomarkers of prognostic value, whereas colonic IL-38 seems to be a reliable and independent biomarker in predicting the 5-year survival post-surgery in CRC. However, there is room for improvement in available studies, including the extension of these studies to different regions/countries incorporating different races, evaluation of the role of multi-drug resistance, and different subsets of CRC. It would be useful to determine the kinetics of circulating IL-38 and its relationship with drug resistance/targeted therapy. The measurement of colonic IL-38 at the molecular and cellular level is required to explore the contribution of IL-38 pathways during the development of CRC. These approaches could provide insight for the development of personalized medicine.

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confidence: 99%

The Role of IL-37 and IL-38 in Colorectal Cancer

Deng

Cui

et al. 2022

Front. Med.

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“…In DM, TCF7 and GNAI2 were also upregulated, in addition to LAIR2 and IFITM3 . The known atherosclerosis gene IL32 27 was downregulated in DM+ compared to non-DM participants ( Figure 5B ). More systematic investigation of the overlap showed that 31 genes were significantly upregulated in both CAD and DM ( Table S6 for the genes expressed in at least 20% of the higher expressing cell type (pct.1 > 0.2).…”

Section: Resultsmentioning

confidence: 98%

“…IL-32 is a known atherosclerosis genes. 27,42 KLF2 is involved in Treg development, 43 but the detailed function of KLF2 in CD4T cells in the development of CAD has not been reported. CD48 on T cells enhances TCR signaling through cis interactions with CD2, LAT and Lck.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells

Saigusa

Vallejo

Gulati

et al. 2022

Preprint

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BackgroundDespite the decades-old knowledge that diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD), the reasons for this association are only partially understood. Among the immune cells involved in CVD development, accumulating evidence supports the critical role of T cells as drivers and modifiers of this condition. CD4+ T cells are commonly found in atherosclerotic plaques. The activity and distribution of CD4+ T cell subsets differs between the sexes.MethodsPeripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by single cell RNA sequencing (scRNA-Seq, ∼200,000 cells) combined with 49 protein markers (CITE-Seq). Coronary artery disease (CAD) was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD-. Four pairs of groups were matched for clinical and demographic parameters. To test how DM changed cell proportions and gene expression, we compared matched groups of diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 61 mostly statin-treated coronary artery disease patients with and without DM.ResultsWe identified 16 clusters in CD4 T cells. The proportion of cells in CD4 cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. The proportions of cells in CD4T2, CD4T11, CD4T16 were increased and CD4T13 was decreased in CAD+ among DM+Statin+ participants. CD4T12 was increased in DM+ participants. In female participants, CD4T8, 12, and 13 were decreased compared to in male participants. In CD4 T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature.ConclusionsWe conclude that CAD and DM are clearly reflected in PBMC transcriptomes and that significant differences exist between women and men and between subjects treated with statins or not.

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“…In DM, TCF7 and GNAI2 were also upregulated, in addition to LAIR2 and IFITM3 . The known atherosclerosis gene IL32 [ 21 ] was upregulated in DM- subjects compared to DM+ participants ( Figure 5 B). More systematic investigation of the overlap showed that 31 genes were significantly upregulated in both CAD and DM (see Table S6 for the genes expressed in at least 20% of the higher expressing cell type (pct.1 > 0.2)).…”

Section: Resultsmentioning

confidence: 99%

Sex Differences in Coronary Artery Disease and Diabetes Revealed by scRNA-Seq and CITE-Seq of Human CD4+ T Cells

Saigusa

Vallejo

Gulati

et al. 2022

IJMS

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Despite the decades-old knowledge that males and people with diabetes mellitus (DM) are at increased risk for coronary artery disease (CAD), the reasons for this association are only partially understood. Among the immune cells involved, recent evidence supports a critical role of T cells as drivers and modifiers of CAD. CD4+ T cells are commonly found in atherosclerotic plaques. We aimed to understand the relationship of CAD with sex and DM by single-cell RNA (scRNA-Seq) and antibody sequencing (CITE-Seq) of CD4+ T cells. Peripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by scRNA-Seq combined with 49 surface markers (CITE-Seq). CAD severity was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD−. Four pairs of groups were matched for clinical and demographic parameters. To test how sex and DM changed cell proportions and gene expression, we compared matched groups of men and women, as well as diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 16 women and 45 men with and without coronary artery disease and with and without DM. We identified 16 clusters in CD4+ T cells. The proportion of cells in CD4+ effector memory cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. This same cluster, CD4T8, was significantly decreased in female participants, along with two other CD4+ T cell clusters. In CD4+ T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature. We conclude that (1) CAD and DM are clearly reflected in PBMC transcriptomes, and (2) significant differences exist between women and men and (3) between subjects with DM and non-DM.

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Clinical Implications of IL-32, IL-34 and IL-37 in Atherosclerosis: Speculative Role in Cardiovascular Manifestations of COVID-19

Cited by 24 publications

References 117 publications

The Role of IL-37 and IL-38 in Colorectal Cancer

The Role of IL-37 and IL-38 in Colorectal Cancer

Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells

Sex Differences in Coronary Artery Disease and Diabetes Revealed by scRNA-Seq and CITE-Seq of Human CD4+ T Cells

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