No abstract

Mammalian NLR proteins contribute to the regulation and induction of innate and adaptive immunity in mammals although the function of about half of the currently identified NLR proteins remains poorly characterized. Here we analysed the function of the primate-specific NLRP11 gene product. We show that NLRP11 is highly expressed in immune cells, including myeloid cells, B cells and some B cell lymphoma lines. Overexpression of NLRP11 in human cells did not trigger key innate immune signalling pathways including NF-κB and type I interferon responses. NLRP11 harbours a pyrin domain (PYD), which is responsible for inflammasome formation in related NLR proteins. However, NLRP11 did neither interact with the inflammasome adaptor protein ASC nor did it trigger caspase-1 activation. By contrast, expression of NLRP11 specifically repressed NF-κB and type I interferon responses, two key innate immune pathways involved in inflammation. This effect was independent of the PYD domain and ATPase activity of NLRP11. SiRNA-mediated knock-down of NLRP11 in human myeloid THP1 cells validated these findings and revealed enhanced lipopolysaccharide (LPS) and Sendai Virus (SeV)-induced cytokine and interferon responses, respectively in cells with reduced NLRP11 expression. In summary, our work identifies a novel role of NLRP11 in the regulation of inflammatory responses in human cells.An inflammatory response is triggered in response to cell damage and to defend against invading pathogens. In mammals, this is mediated by the activation of cellular pathways cumulating into the release of cytokines, chemokines and interferons. Downstream, this orchestrates recruitment of effector cells, alerts a systemic response and restores tissue homeostasis (1). Activation of pattern-recognition receptors (PRRs 2 ), expressed in and on host cells, which respond towards pathogen-derived substances, cell damage and stress, initiate this response. On the cellular level, inflammation is mediated by the activation of proinflammatory signaling cascades such as the activation of caspase-1, NF-κB, IRFs, amongst others. Chronic In humans, the TLR, NLR and C-type lectin family members are the most relevant PRRs. Many mammalian NLR proteins have been associated with multiple functions in inflammation and innate and adaptive immune responses (4) and dysfunctions in NLRs are associated with a range of diseases including Crohn's disease, periodic fever syndromes and Blau Syndrom (5), highlighting their physiologic relevance NLR proteins have a typical tripartite domain architecture and can be classified functionally according to their N-terminal domain which is, in most cases a CARD or PYD domain (6). Most but not all PYD-containing NLRs can interact with the adaptor molecule ASC to form high molecular weight complexes in cells, referred to as inflammasomes, which function as a platform for the activation of caspase-1 and subsequent IL-1β and IL-18 processing. The NLR family-member pyrin domain-containing protein 11 (NLRP11, NALP11, NOD17, PYPAF6, PAN...

The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell,, and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective orthologs Emb, Cdm, and Kap-α3. While overexpression of CRM1/Emb demonstrated positive effects in, KPNA3/Kap-α3 emerged as the most promising target, as knockdown via multiple RNAi lines demonstrated its ability to shuttle both truncated and full-length expanded ataxin-3, rescue neurodegeneration, restore photoreceptor formation, and reduce aggregation. Furthermore, knockout in SCA3 mice resulted in an amelioration of molecular and behavioral disturbances such as total activity, anxiety, and gait. Since KPNA3 is known to function as an import protein and recognize nuclear localization signals (NLSs), this work unites ataxin-3 structure to the nuclear pore machinery and provides a link between karyopherins, NLS signals, and polyglutamine disease, as well as demonstrates that KPNA3 is a key player in the pathogenesis of SCA3.

Background and Aims: As mast cells (MC) serve as a link between mucosal immune activity and the nervous system, it is likely they also play a role in the pathogenesis of irritable bowel syndrome (IBS). This connection might be an important factor in the development of IBS-related symptoms. Method: This overview comprises 36 case-control studies published from 2000 to 2018 that investigated MC in bowel biopsies of IBS patients and controls. The studies were selected from PubMed, EMBASE, Central, SemanticScholar by an electronic search, performed using RISMed R package. Results: Significantly increased mucosal MC counts/or density in IBS patients compared to controls was observed in 30 studies. Five studies reported no differences and only one of the studies found a decreased amount of MC in an IBS patient. Furthermore, 15 studies made a statement regarding the correlation between the amount of MC and IBS associated symptoms. A significant positive correlation between MC count and IBS-associated symptoms was found in six investigations. A negative correlation was not reported. Conclusion: The results support the idea that MC are involved in IBS pathophysiology as key players in the interplay between psychological factors and the frequency and severity of IBS symptoms.

Allergic diseases are known to vary in the severity of their symptoms throughout the day/night cycle. This rhythmicity is also observed in mast cell function and responsiveness. Mast cells are key effector cells of allergic reactions and release cytokines, chemokines, and important inflammatory mediators such as histamine, which have been shown to display diurnal variation. Recent research clarified that mast cells are controlled by their internal clock—which is regulated by a specific set of clock genes—as well as external factors such as light sensed by the suprachiasmatic nuclei, hormonal status, or diet. Here, we give an overview of the connections between circadian clock, mast cells, and allergic disease. Further work aimed at studying the role of chronotherapy/chronomedicine should take into account this rhythmic nature of not only mast cells but also the immune responses generated by mast cell signaling.

Our study provides novel insights into the mechanisms of action of divalproex sodium as a possible treatment for SCA3, beyond the known regulation of transcription.

NOD-like receptors (NLR) are critical regulators of innate immune signaling. The NLR family consists of 22 human proteins with a conserved structure containing a central oligomerization NACHT domain, an N-terminal interaction domain, and a variable number of C-terminal leucine-rich repeats. Most NLR proteins function as cytosolic pattern recognition receptors with activation of downstream inflammasome signaling, NF-κB, or MAPK activation. Although NLRP10 is the only NLR protein lacking the leucine rich repeats, it has been implicated in multiple immune pathways, including the regulation of inflammatory responses toward Leishmania major and Shigella flexneri infection. In this study, we identify Abin-1, a negative regulator of NF-κB, as an interaction partner of NLRP10 that binds to the NACHT domain of NLRP10. Using S. flexneri as an infection model in human epithelial cells, our work reveals a novel function of NLRP10 in destabilizing Abin-1, resulting in enhanced proinflammatory signaling. Our data give insight into the molecular mechanism underlying the function of NLRP10 in innate immune responses.