Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies

NLRP3-inflammasome activating DAMPs stimulate an inflammatory response in glia in the absence of priming which contributes to brain inflammation after injury

Inflammation in the absence of infection (sterile inflammation) contributes to acute injury and chronic disease. Cerebral ischemia is a devastating condition in which the primary injury is caused by reduced blood supply and is therefore sterile. The cytokine interleukin-1β (IL-1β) is a key contributor to ischemic brain injury and central inflammatory responses. The release of IL-1β is regulated by the protease caspase-1, and its activating complex, the inflammasome. Of the known inflammasomes the best characterized, and one that is perceived to sense sterile injury is formed by a pattern recognition receptor called NOD-like receptor pyrin domain containing three (NLRP3). A key feature of NLRP3-inflammasome dependent responses in vitro in macrophages is the requirement of an initial priming stimulus by a pathogen (PAMP), or damage associated molecular pattern (DAMP) respectively. We sought to determine the inflammatory responses of NLRP3-activating DAMPs on brain derived mixed glial cells in the absence of an initial priming stimulus in vitro. In cultured mouse mixed glia the DAMPs ATP, monosodium urate, and calcium pyrophosphate dehydrate crystals had no effect on the expression of IL-1α or IL-1β and induced release only when the cells were primed with a PAMP. In the absence of priming, these DAMPs did however induce inflammation via the production of IL-6 and CXCL1, and the release of the lysosomal protease cathepsin B. Furthermore, the acute phase protein serum amyloid A (SAA) acted as a priming stimulus on glial cells resulting in levels of IL-1 expression comparable to those induced by the PAMP lipopolysaccharide. In vivo, after cerebral ischemia, IL-1 production contributed to increased IL-6 and CXCL1 since these cytokines were profoundly reduced in the ischemic hemispheres from IL-1α/β double KO mice, although injury-induced cytokine responses were not abolished. Thus, DAMPs augment brain inflammation by directly stimulating production of glial derived inflammatory mediators. This is markedly enhanced by DAMP-induced IL-1-release-dependent responses that require a sterile endogenous priming stimulus such as SAA

Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification

From Wiley via Jisc Publications RouterHistory: received 2020-03-02, rev-recd 2020-10-12, accepted 2020-11-02, pub-electronic 2020-11-21, pub-print 2021-05Article version: VoRPublication status: PublishedFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N029992/1The release of interleukin (IL)‐1β from primary human monocytes in response to extracellular LPS occurs through the NACHT, LRR and PYD domains‐containing protein 3 (NLRP3) inflammasome. In primary monocytes, in response to LPS, NLRP3 inflammasome activation is characterized by an independence of K+ efflux and ASC speck formation and has been termed the ‘alternative’ pathway. Here, we report that pharmacological inhibition of V‐ATPase with bafilomycin A1 exacerbated LPS‐induced NLRP3 inflammasome activation in primary human monocytes. Inhibition of V‐ATPase in the presence of extracellular LPS led to NLRP3‐dependent, K+ efflux‐independent, ASC oligomerization and caspase‐1 activation. Although V‐ATPases are required for lysosomal acidification, we found that acidic lysosomal pH and protease activity were dispensable for this altered response, suggesting that V‐ATPase inhibition triggered alternative signalling events. Therefore, V‐ATPases may serve additional roles during NLRP3 inflammasome activation in primary human monocytes

Regulation of NLRP3 activation by the ubiquitin system

AbstractInflammasomes, molecular complexes activated in response to pathogens or injury, are involved in the activation and release of the proinflammatory cytokine interleukin-1β. Inflammasome activation is tightly controlled and its dysregulation is associated with the development of inflammatory disorders. Ubiquitination, the conjugation of ubiquitin to a protein, is a post-translational protein modification essential for a wide variety of cellular processes. What was initially considered to be just a signal for protein degradation has become a major regulator for signalling pathways that is also involved in the regulation of NLRP3 inflammasome activation. Similarly to the inflammasome, dysregulation of ubiquitin signalling is associated with the initiation and development of pathologies including immune disorders such as arthritis or lupus erythematous, highlighting the relevance of these systems in the inflammatory processes. How the ubiquitin system regulates the NLRP3 inflammasome is discussed here</jats:p