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

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.

Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD

“…Cytokines and chemokines in the liver are soluble mediators of local and systemic inflammation ( Figure 2(a) ) [ 8 , 43 , 56 , 57 ]. To analyze liver inflammation, we used IPA and classified 53 cytokines and chemokines from 1376 innate immune genes [ 58 , 59 ] from the Innate Immunity Database [ 58 , 60 ]. Human NASH upregulated six (11.3%) and four (7.5%) out of 53 innate immune cytokines and chemokines, respectively ( Figure 2(b) ).…”

“…We acknowledge that carefully designed in vitro and in vivo experimental models will be needed to verify all the findings. Nevertheless, our findings provide novel insights on the roles of proinflammatory cytokines and chemokines [ 58 , 59 ] and canonical secretome [ 61 , 115 , 116 ], canonical and noncanonical inflammasome pathways, TI enzymes, and lipid peroxidation enzymes in promoting NASH/NAFLD progression as well as novel targets for the future therapeutic interventions for NASH/NAFLD, metabolic diseases, transplantation, and cancers.…”

Organelle Crosstalk Regulators Are Regulated in Diseases, Tumors, and Regulatory T Cells: Novel Classification of Organelle Crosstalk Regulators

“…These mechanisms include innate immune activation (11) of endothelial cells (ECs) (3,(12)(13)(14)(15) promoting EC injury (16); Ly6Chigh inflammatory mouse monocyte and CD40 + human monocyte differentiation (7,(17)(18)(19); disease reprogrammed macrophages (20)(21)(22); cytokine and secretome regulation (23)(24)(25)(26)(27)(28)(29)(30); decreased/transdifferentiated CD4 + Foxp3 + regulatory T cells (Treg) (24,(31)(32)(33)(34); and impaired vascular repairability of bone marrow-derived progenitor cells (35,36). In addition, we recently proposed new models such as intracellular organelle dangers (37) and reactive oxygen species (ROS) as an integrated sensing system for metabolic homeostasis and alarming (38), which indicated that metabolic reprogramming and dysfunction trigger mitochondrial (MT) ROS (4,(39)(40)(41)(42); caspase-1/inflammasome activation (8, 10) downregulated histone modification enzymes (43) and increased expressions of trained immunity pathway enzymes (22,39,(44)(45)(46)…”

Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation

“…Due to its vast coverage and the nature of being the first cell type to encounter any PAMPs/DAMPs in the blood circulation, the endothelium (endothelial cells, EC) [ 46 ] could function as the primary intravascular sentinel system [ [47] , [48] , [49] ]. Thus, we compared EC to prototypic innate immune cells such as macrophages [ 50 ] in 13 innate immune features, and proposed a new paradigm that EC are innate immune cells [ 2 , 3 , 51 ], which was further supported by our new paper examining the expression changes of 1311 innate immune regulatomic genes (IGs) [ 52 , 53 ] in ECs and reviews [ 54 , 55 ]. We introduced new concepts that mitochondrial reactive oxygen species (mtROS) and proton leak mediate physiological activation and pathological activation of EC [ [56] , [57] , [58] , [59] ]; ROS systems are a new integrated network for sensing homeostasis and alarming stresses [ 60 ].…”