The modulation of immune cell death in connection to microRNAs and natural products

Abstract

Immunogenic cell death (ICD) spatiotemporally regulates damage-associated molecular patterns (DAMPs) derived from dying cancer cells to signal the immune response. Intriguingly, these DAMPs and cytokines also induce cellular responses in non-immune cells, particularly cancer cells. Several ICD-modulating natural products and miRNAs have been reported to regulate the DAMP, cytokine, and cell death responses, but they lack systemic organization and connection. This review summarizes the impacts of natural products and miRNAs on the DAMP and cytokine responses and cancer cell death responses (apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis). We establish the rationale that ICD inducers of natural products have modulating effects on miRNAs, targeting DAMPs and cytokines for immune and cancer cell death responses. In conclusion, DAMP, cytokine, and cell death responses are intricately linked in cancer cells, and they are influenced by ICD-modulating natural products and miRNAs.

Keywords: DAMPs; ICD; cytokines; microRNAs; natural products; targets.

Figure 1

Protein signaling pathway involving both DAMPs and selected cytokines in ICD modulation. ICD inducer triggers HMGB1 secretion, CALR surface exposure, HSPA4/HSP90AA1 surface exposure and secretion, and inflammatory cytokine secretion from dying cancer cells or damaged cells. Subsequently, HSPA4/HSP90AA1 and inflammatory cytokines can activate both NK and DC cells. NK cells secrete INFG and TNF to activate Th1 and Th17 to secrete IFNG and IL17A, respectively. Moreover, DC cells secrete IL12A and IL12B to activate Th1 cells and secrete IL6 and IL23A to activate CTL cells for IFNG secretion.

Figure 2

Arrangement of this review. Using Google Scholar, we organized natural products with ICD-inducing functions and their ICD targets, such as DAMPs and cytokines [ Table 1 (T1)]. ICD-modulating miRNAs that regulate DAMPs and cytokines were also retrieved [ Tables 2 and 3 (T2, T3)]. Based on our searches in Google Scholar and miRDB (270), the potential ICD targets (DAMPs (HMGB1, CALR, HSP1A, HSP1B, HSP90AA1, and HSP90B1) [ Figure 3 (F3)] and cytokines [IL6, IL8, IL12A, IL12B, IL17A, IL23, IFNB1, INFG, and TNF)] for these miRNAs were collected ( Tables 2 , 3 ). Moreover, the DAMP-modulated miRNAs ( Table 1 ) targeting DAMPs are shown. In comparison, the functions of cytokine-modulated miRNAs ( Table 2 ) are presented. For DAMP-modulating miRNAs, the immune and cell death responses were categorized ( Table 2 ). Cell death responses, such as apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis, were also retrieved. For cytokine-modulating miRNAs, their immune responses and expression levels in cancer cells were categorized [ Table 3 (T3)]. Finally, we ascertained the relationship between ICD inducers of natural products and ICD-modulating miRNAs [ Table 4 (T4) and Figure 4 (F4)].

Figure 3

Classification of ICD inducers of natural products into different classes based on their targeting. The potential interaction for targets was analyzed by STRING database. All the information was derived from Table 1 . The symbols of “T” and “arrow-line” indicate that natural products downregulate and upregulate their targets. HSP70 and HSP90 are labeled with HSPA4 and HSP90AA1 in the network, respectively. Dox, Doxorubicin; Shik, Shikonin; Digi, Digitoxin; Digo, Digoxin; Ouab, Ouabain; LanC, Lanatoside C; Pac, Paclitaxel; Col, Colchicine; EpoB, Epothilone B; Wogo, Wogonin; Dau, Daunorubicin; Lina, Linalool; Caps, Capsaicin; Asta, Astaxanthin; Para, Paramylon; Cphy, C-phycocyanin; Fuco, Fucoidan; Sep, Septacidin; Doco, Docosahexaenoic acid; Bleo, Bleomycin; Dact, Dactinomycin.

Figure 4

Relationship between ICD inducers of natural products and the regulation of ICD-modulating miRNAs.