Ultrasound May Suppress Tumor Growth, Inhibit Inflammation, and Establish Tolerogenesis by Remodeling Innatome via Pathways of ROS, Immune Checkpoints, Cytokines, and Trained Immunity/Tolerance

Author:

Yang Qian123ORCID,Zhang Ruijing14ORCID,Tang Peng5ORCID,Sun Yu1ORCID,Johnson Candice1ORCID,Saredy Jason6ORCID,Wu Susu1ORCID,Wang Jiwei1ORCID,Lu Yifan1ORCID,Saaoud Fatma1ORCID,Shao Ying1ORCID,Drummer Charles1ORCID,Xu Keman1ORCID,Yu Daohai7ORCID,Li Rongshan4ORCID,Ge Shuping3ORCID,Jiang Xiaohua16ORCID,Wang Hong6ORCID,Yang Xiaofeng16ORCID

Affiliation:

1. Centers for Cardiovascular Research and Inflammation, Translational, & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA

2. Department of Ultrasonic Diagnosis and Treatment Center, XiAn International Medical Center Hospital, XiAn, China

3. Heart Center, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA

4. Department of Nephrology, Second Hospital of Shanxi Medical University, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, China

5. Department of Orthopedics, Beijing Charity Hospital of China Rehabilitation Research Center, Beijing, China

6. Metabolic Disease Research & Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA

7. Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA

Abstract

Background. The immune mechanisms underlying low-intensity ultrasound- (LIUS-) mediated suppression of inflammation and tumorigenesis remain poorly determined. Methods. We used microarray datasets from the NCBI GEO DataSet repository and conducted comprehensive data-mining analyses, where we examined the gene expression of 1376 innate immune regulators (innatome genes (IGs) in cells treated with LIUS. Results. We made the following findings: (1) LIUS upregulates proinflammatory IGs and downregulates metastasis genes in cancer cells, and LIUS upregulates adaptive immunity pathways but inhibits danger-sensing and inflammation pathways and promote tolerogenic differentiation in bone marrow (BM) cells. (2) LIUS upregulates IGs encoded for proteins localized in the cytoplasm, extracellular space, and others, but downregulates IG proteins localized in nuclear and plasma membranes, and LIUS downregulates phosphatases. (3) LIUS-modulated IGs act partially via several important pathways of reactive oxygen species (ROS), reverse signaling of immune checkpoint receptors B7-H4 and BTNL2, inflammatory cytokines, and static or oscillatory shear stress and heat generation, among which ROS is a dominant mechanism. (4) LIUS upregulates trained immunity enzymes in lymphoma cells and downregulates trained immunity enzymes and presumably establishes trained tolerance in BM cells. (5) LIUS modulates chromatin long-range interactions to differentially regulate IGs expression in cancer cells and noncancer cells. Conclusions. Our analysis suggests novel molecular mechanisms that are utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.

Publisher

Hindawi Limited

Subject

Immunology,General Medicine,Immunology and Allergy

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