5-Aminolevulinic Acid-Mediated Sonodynamic Therapy Alleviates Atherosclerosis via Enhancing Efferocytosis and Facilitating a Shift in the Th1/Th2 Balance Toward Th2 Polarization

Abstract

Background/Aims: We and other groups have demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (ALA-SDT) induces macrophage and foam cell apoptosis and stabilizes atherosclerosis (AS) plaques in animal models. Lymphocytes also play vital roles in the development of AS. The primary purpose of the present study was to investigate the effects of ALA-SDT on T helper (Th) cell fate and function, Th subset differentiation, and atherosclerotic lesion stability. Methods: We utilized ALA-SDT on Western diet-fed apoE^-/-mice in vivo and human Jurkat cells in vitro. Hematoxylin and eosin staining and TUNEL assays were used to evaluate the atherosclerotic plaque size and apoptosis within the atheroma. ALA induced cytotoxicity on cultured Jurkat cells was determined with CCK-8 assay. To address the mechanisms, levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and mitochondrial permeability transition pore (MPTP) opening were evaluated by staining with fluorescent probes. Western blot analysis and confocal microscopy were used to analyze the protein levels of caspases, Bax and cytochrome c and the release of cytochrome c. Cell apoptosis and necrosis and phagocytosis were examined by flow cytometry. ELISAs and immunofluorescent staining were used to assess the corresponding cytokine levels and Th subset cell numbers within the atheroma. Results: Our studies revealed that ALA-SDT significantly enhanced CD4⁺ cell apoptosis and macrophage-mediated phagocytosis and hence reduced the necrotic core size. ALA-SDT activated the mitochondrial apoptotic signaling pathway with minimal necrosis in Jurkat cells. ALA-SDT inhibited the Th1 response and enhanced the Th2 response. These effects of ALA-SDT were mediated primarily through the generation of ROS. Conclusion: ALA-SDT alleviates AS by enhancing cytotoxic effects on Th cells, subsequently stimulating efferocytosis and facilitating a shift in the Th1/Th2 balance toward Th2 cells, a discovery that might help elucidate the mechanism underlying SDT as a potential treatment to prevent atherothrombotic events.

Vascular inflammation in moderate‐to‐severe atopic dermatitis is associated with enhanced Th2 response

“…65 However, the role of the Th2 immune response in atherosclerosis has been controversial. 66 While some studies report a protective effect, 67,68 others have demonstrated a pro-atherogenic impact. [69][70][71] Of note, increased expression of CCL17 and CCL22 has been found in atherosclerotic lesions, with one study suggesting the role of CCL17 in driving atherosclerosis via restraining regulatory T-cell homeostasis.…”

Astragali Radix-Coptis Rhizoma Herb Pair Attenuates Atherosclerosis in ApoE-/- Mice by Regulating the M1/M2 and Th1/Th2 Immune Balance and Activating the STAT6 Signaling Pathway

“…e decrease in AS is related to the decrease in the 1/ 2 ratio [36]. e 1/ 2 balance may be targeted in AS prevention and treatment research [37]. Our research first found that the ARCR herb pair slowed the development of AS in ApoE-/-mice, stabilized plaques, and regulated the balance of serum inflammatory factors.…”

T cell co-stimulator inducible co-stimulatory (ICOS) exerts potential anti-atherosclerotic roles through downregulation of vascular smooth muscle phagocytosis and proliferation

“…The implications of Th2 cells are more ambiguous, as they have been involved in AS resistance, but at times have also shown a slight atherosclerogenic effect. By contrast, regulatory T cells reduce the formation of AS and play a protective role (34)(35)(36)(37)(38)(39). The co-stimulatory molecules involved in immune synapses between T cells and APCs can regulate 16) rats; nuclei were counterstained with DAPI.…”