1. Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death
K Hayashi, F Nikolos, Y C Lee, A Jain, E Tsouko, H Gao, A Kasabyan, H E Leung, A Osipov, S Y Jung, A V Kurtova, K S Chan Nat Commun. 2020 Dec 7;11(1):6299. doi: 10.1038/s41467-020-19970-9.
Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.
2. The mechanism of HMGB1 secretion and release
Ruochan Chen, Rui Kang, Daolin Tang Exp Mol Med. 2022 Feb;54(2):91-102. doi: 10.1038/s12276-022-00736-w. Epub 2022 Feb 25.
High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 is a DNA chaperone that maintains the structure and function of chromosomes. In the cytoplasm, HMGB1 can promote autophagy by binding to BECN1 protein. After its active secretion or passive release, extracellular HMGB1 usually acts as a damage-associated molecular pattern (DAMP) molecule, regulating inflammation and immune responses through different receptors or direct uptake. The secretion and release of HMGB1 is fine-tuned by a variety of factors, including its posttranslational modification (e.g., acetylation, ADP-ribosylation, phosphorylation, and methylation) and the molecular machinery of cell death (e.g., apoptosis, pyroptosis, necroptosis, alkaliptosis, and ferroptosis). In this minireview, we introduce the basic structure and function of HMGB1 and focus on the regulatory mechanism of HMGB1 secretion and release. Understanding these topics may help us develop new HMGB1-targeted drugs for various conditions, especially inflammatory diseases and tissue damage.
3. DAMP-sensing receptors in sterile inflammation and inflammatory diseases
Tao Gong, Lei Liu, Wei Jiang, Rongbin Zhou Nat Rev Immunol. 2020 Feb;20(2):95-112. doi: 10.1038/s41577-019-0215-7. Epub 2019 Sep 26.
The innate immune system has the capacity to detect 'non-self' molecules derived from pathogens, known as pathogen-associated molecular patterns, via pattern recognition receptors. In addition, an increasing number of endogenous host-derived molecules, termed damage-associated molecular patterns (DAMPs), have been found to be sensed by various innate immune receptors. The recognition of DAMPs, which are produced or released by damaged and dying cells, promotes sterile inflammation, which is important for tissue repair and regeneration, but can also lead to the development of numerous inflammatory diseases, such as metabolic disorders, neurodegenerative diseases, autoimmune diseases and cancer. Here we examine recent discoveries concerning the roles of DAMP-sensing receptors in sterile inflammation and in diseases resulting from dysregulated sterile inflammation, and then discuss insights into the cross-regulation of these receptors and their ligands.
