Role of scavenger receptors as damage-associated molecular pattern receptors in Toll-like receptor activation

Abstract

Damage-associated molecular patterns (DAMPs) have been implicated in sterile inflammation in various tissue injuries. High-mobility group box 1 (HMGB1) is a representative DAMP, and has been shown to transmit signals through receptors for advanced glycation end products (RAGEs) and TLRs, including TLR2 and TLR4. HMGB1 does not, however, bind to TLRs with high affinity; therefore, the mechanism of HMGB1-mediated TLR activation remains unclear. In this study, we found that fluorescently labeled HMGB1 was efficiently internalized into macrophages through class A scavenger receptors. Although both M1- and M2-type macrophages internalized HMGB1, only M1-type macrophages secreted cytokines in response to HMGB1. The pan-class A scavenger receptor competitive inhibitor, maleylated bovine serum albumin (M-BSA), inhibited HMGB1 internalization and reduced cytokine production from macrophages in response to HMGB1 but not to LPS. The C-terminal acidic domain of HMGB1 is responsible for scavenger receptor-mediated internalization and cytokine production. HMGB1 and TLR4 co-localized in macrophages, and this interaction was disrupted by M-BSA, suggesting that class A scavenger receptors function as co-receptors of HMGB1 for TLR activation. M-BSA ameliorated LPS-induced sepsis and dextran sulfate sodium (DSS)-induced colitis models in which HMGB1 has been shown to play progressive roles. These data suggest that scavenger receptors function as co-receptors along with TLRs for HMGB1 in M1-type inflammatory macrophages.

Galectin 3 protects from cisplatin-induced acute kidney injury by promoting TLR-2-dependent activation of IDO1/Kynurenine pathway in renal DCs

“…It is well known that expression of TLR-2 is needed for optimal AGE receptor-dependent generation of immunosuppressive phenotype in renal DCs 2-3, 70-71. DAMPs, released from CDDP-injured PTECs, bind to TLR-2 which interacts with activated AGE receptors to induce development of immature, tolerogenic phenotype in DCs 2, 70-72.…”

“…It is well known that expression of TLR-2 is needed for optimal AGE receptor-dependent generation of immunosuppressive phenotype in renal DCs 2-3, 70-71. DAMPs, released from CDDP-injured PTECs, bind to TLR-2 which interacts with activated AGE receptors to induce development of immature, tolerogenic phenotype in DCs 2, 70-72. In line with these findings, activation of TLR-2 down-regulates expression of co-stimulatory (CD80 and CD86) and MHC-class II molecules on DCs, reduces production of Th1 (IL-12) and Th17-related (IL-1, IL-6, IL-23, TGF-β) cytokines and attenuates capacity of DCs to induce differentiation of naïve CD4+ T cells in effector IFN-γ-producing Th1 and IL-17-producing Th17 cells 2, 70-72.…”

The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease

“…TLRs are fundamental to innate immunity, as they recognize pathogen-associated molecular patterns (highly conserved, distinct motifs present on pathogens) and respond by exerting robust inflammatory mechanisms in an effort to neutralize and eliminate pathogenic invasion [74][75][76]. Furthermore, TLRs are able to respond to danger-associated molecular patterns (host-derived endogenous alarmins), released by damaged, dying, or necrotic cells, independent of pathogenic infection [77]. The end product of sterile inflammation, either through the myeloid-differentiation factor-88 (MyD88)-dependent pathway (TLR1, 2, 4-10) [78] or the MyD88-independent pathway (TLR3 and 4) [79], is ubiquitous among TLRs [80].…”

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

“…G-quadruplex DNA aptamers become interesting therapeutic and diagnostic alternatives to antibodies because of their high thermal stability, resistance to numerous serum nucleases, increased cellular uptake, and ease of chemical modification [61]. In the context of our work, it should be noted that DNA G-tracts are recognized by scavenger receptors, which are expressed on the surface of immune cells and can act as phagocytic receptors, as well as TLR co-receptors facilitating ODN uptake [62,63]. It has been shown synthetic ODNs consisting of a repeating telomere TTAGGG sequence can neutralize the immune activation induced by bacterial CpG-ODNs [11].…”