Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs. 

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Mitochondrial control of inflammation

The paradigm of surface-expressed programmed death ligand 1 (PDL1) signalling to immune cell programmed death 1 (PD1) to inhibit antitumour immunity has helped to develop effective and revolutionary immunotherapies using antibodies blocking these cell-extrinsic interactions. The recent discovery of cancer cell-intrinsic PDL1 signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation. Many such effects are PD1-independent. These insights demonstrate that the prevailing cell-extrinsic PDL1 signalling paradigm is useful, but incomplete in important respects. This Perspective discusses historical and recent advances in understanding cancer cell-intrinsic PDL1 signals, mechanisms for signal controls and important immunopathologic consequences including resistance to cytotoxic agents, targeted small molecules and immunotherapies. Cancer cell-intrinsic PDL1 signals present novel drug discovery targets and also have potential as reliable treatment response biomarkers. Cancer cell-intrinsic PD1 signals and cell-intrinsic PDL1 signals in non-cancer cells are discussed briefly, as are PDL1 signals from soluble and vesicle-bound PDL1 and PDL1 isoforms. We conclude with suggestions for addressing the most pressing challenges and opportunities in this rapidly developing field. 

Programmed death ligand 1 signals in cancer cells

The classic mode of STING activation is through binding the cyclic dinucleotide 2′3′-cyclic GMP–AMP (cGAMP), produced by the DNA sensor cyclic GMP–AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity labelling screen followed by quantitative proteomics, we identify the lysosomal membrane protein Niemann–Pick type C1 (NPC1) as a cofactor in the trafficking of STING. NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Notably, we find that knockout of Npc1 ‘primes’ STING signalling by physically linking or ‘tethering’ STING to SREBP2 trafficking. Loss of NPC1 protein also ‘boosts’ STING signalling by blocking lysosomal degradation. Both priming and boosting of STING signalling are required for severe neurological disease in the Npc1−/− mouse. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1−/− mice, leading to improved motor function. Our study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann–Pick disease type C. The lysosomal protein Niemann–Pick type C1 (NPC1) is identified as a cofactor in the trafficking of STING, and loss of NPC1 is shown to both ‘prime’ and ‘boost’ STING signalling leading to neurological disease.

Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.

Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis1. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING2,3. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer4, and, although they have been implicated in metastasis5, it is not known why loss-of-function mutations do not arise in primary tumours4. Here we show that inactivation of cGAS-STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6-STAT3-mediated signalling, which depends on the cGAS-STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS-STING signalling and explains why the cGAS-STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R. 

https://pure.rug.nl/ws/files/229114659/s41586_022_04847_2_1_.pdf

cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers

The cGAS-STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage Underlying this broad involvement of the cGAS-STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules Insights into the structural and molecular biology of the cGAS-STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS-STING axis in a number of inflammatory diseases in humans Here, we outline the principal elements of the cGAS-STING signalling cascade and discuss the general mechanisms underlying the association of cGAS-STING activity with various autoinflammatory, autoimmune and degenerative diseases Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications

/pdf/the-cgas-sting-pathway-as-a-therapeutic-target-in-1ha5zhuhbm.pdf

The cGAS-STING pathway as a therapeutic target in inflammatory diseases.

In one aspect, compounds of Formulae (I) and (II), or pharmaceutically acceptable salts thereof, are featured; Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formulae (I) and (II) can be as defined anywhere herein.

Compounds and compositions for treating conditions associated with NLRP activity

In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: wherein the variables shown in Formula AA can be as defined anywhere herein. Compounds AA are modulators of NLRP1 and/or NLRP3

Sulphonamides and compositions thereof for treating conditions associated with nlrp activity

Provided herein are methods of treating a subject that include administering a therapeutically effective amount of an NLPR3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level. Provided herein are methods of treating a subject, methods of selecting a treatment for a subject, methods of selecting a subject for treatment, and methods of selecting a subject for participation in a clinical study that include the administration of a therapeutically effective amount of an NLRP3 antagonist. Also provided are methods of treating a subject having resistance to an anti-TNFa agent and methods of determining the efficacy of treatment with an anti-TNFα agent. Also provided are methods of treating a subject with a combination of an NLRP3 antagonist and an anti-TNFα agent.

Methods of treating or selecting a treatment for a subject resistant to tnf inhibitor using a nlrp3 antagonist

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.

Katz Jason

Papers

The cGAS-STING pathway as a therapeutic target in inflammatory diseases.

Compounds and compositions for treating conditions associated with NLRP activity

Sulphonamides and compositions thereof for treating conditions associated with nlrp activity

Methods of treating or selecting a treatment for a subject resistant to tnf inhibitor using a nlrp3 antagonist

N-hetaryl-squaramide compounds for treating conditions associated with sting activity