Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Govindarajan, Vaidya; Vaccari, Juan Pablo de Rivero; Keane, Robert W.

doi:10.1186/s12974-020-01944-9

Cited by 64 publications

(44 citation statements)

References 105 publications

(145 reference statements)

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“…IL-18 is a proinflammatory cytokine primarily involved in T helper 1 (Th1) cell and natural killer (NK) cell responses by inducing IFNγ and also has the ability to induce, that is CCL2. 34 It is also, together with IL-1β, processed by the multiprotein complex called the inflammasome, which is believed to contribute to the inflammatory response in MS. 35,36 In the present study, the levels of IL-18 in MS patients were initially lower than in HC, but increased twofold after treatment with IFNβ. This finding is in contrast with other studies who reported increased IL-18 in MS 37,38 with a decrease after treatment with IFNβ, 39 altogether a mirror image of our results.…”

Section: A) Initial Comparison Of Newly Diagnosed Rrms Patients and Healthy Controls P-values For Student's T-test/mann-whitney's Test (#supporting

confidence: 43%

Urokinase, CX3CL1, CCL2, TRAIL and IL‐18 induced by interferon‐β treatment

et al. 2021

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system. The first disease modifying drug that was approved for MS is interferon beta (IFNβ), which has been a mainstay in treatment of MS for more than twenty years. Although the precise mechanisms of IFNβ remain uncertain, several modes of action have been proposed, including inhibition of T-cell activation and proliferation; inhibition of leucocyte migration; and cytokine modulation. 1 In this study, we investigated the effect of IFNβ 1a on a multiplexed panel of 92 proteins associated with inflammation. | MATERIAL AND ME THODS | Ethics approvalWritten informed consent was provided by all of the participants, and the study was approved by the Regional Ethical Board of Uppsala (Dnr 2012/081 and 2013/219).

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Section: A) Initial Comparison Of Newly Diagnosed Rrms Patients and Healthy Controls P-values For Student's T-test/mann-whitney's Test (#supporting

confidence: 43%

Urokinase, CX3CL1, CCL2, TRAIL and IL‐18 induced by interferon‐β treatment

et al. 2021

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“…The inflammasome is a multiprotein complex comprised of a sensor such as a NOD-like receptor (NLR), the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and the inflammatory cysteine aspartase caspase-1 ( Govindarajan et al, 2020 ). We have previously shown that the NRLP1 inflammasome is activated following cerebral ischemia in rodents ( Abulafia et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Netosis and Inflammasomes in Large Vessel Occlusion Thrombi

et al. 2021

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The inflammatory response appears to play a critical role in clotting in which neutrophil extracellular traps (NETs) are the major drivers of thrombosis in acute ischemic stroke (AIS). The inflammasome is an innate immune complex involved in the activation of interleukin (IL)-18 and IL-1β through caspase-1, but whether the inflammasome plays a role in NETosis in AIS remains poorly understood. Here we assessed the levels of inflammasome signaling proteins in NETs and their association with clinical and procedural outcomes of mechanical thrombectomy for AIS. Electron microscopy and immunofluorescence indicate the presence of NETs in thrombi of patients with AIS. Moreover, the inflammasome signaling proteins caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) were also present in clots associated with the marker of NETosis citrullinated histone 3H (CitH3). Analysis of protein levels by a simple plex assay show that caspase-1, ASC and interleukin (IL)-1β were significantly elevated in clots when compared to plasma of AIS patients and healthy controls, while IL-18 levels were lower. Moreover, multivariate analyses show that IL-1β levels in clots contribute to the number of passes to achieve complete recanalization, and that ASC, caspase-1 and IL-18 are significant contributors to time to recanalization. Thus, inflammasome proteins are elevated in NETs present in thrombi of patients with AIS that contribute to poor outcomes following stroke.

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“…Cell death and in ammation are fundamental characteristics in the initiation and development of neurological dysfunction. GSDMD-mediated pyroptosis plays crucial roles in the pathogenesis of multiple neurological diseases and age-related degeneration [33][34][35]. Pyroptosis is a type of lytic programmed cell death, distinguished from apoptosis and necrosis [8,36].…”

Section: The Chemical Composition Of Ea Active Fraction Of Z Bungeanmentioning

confidence: 99%

Ethyl acetate extracts of Bungeanum ameliorates cognitive deficits by suppressing NLRP3 inflammasome-dependent pyroptosis in aging mice

Zhao

Yuan

et al. 2021

Preprint

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Background: The NLRP3-mediated pyroptosis is a key player in the development of the age-associated neurodegenerative disease. Zanthoxylum bungeanum Maxim (Rutaceae), a homologous of medicine and foodstuff, has previously been demonstrated the potential prevention of cognitive dysfunction in aging mice. However, it is still unknown which fraction is the material basis responsible for their therapeutic effects and whether Z. bungeanum could confer anti-cognitive deficits activity via restraining NLRP3-mediated pyroptosis. Thus, in the current study, we explored the active fraction of Z. bungeanum against cognitive deficits and its underlying mechanism.Methods: In the present study, the D-galactose-induced mouse model of aging was established to explore the effect of cognitive impairment of four fractions of Z. bungeanum, including petroleum ether (PE), methylene chloride (DCM), ethyl acetate (EA), and n-butanol (N-BAI). We next activated the NLRP3 inflammasome in BV-2 microglia cells to investigate the mechanisms for the neuroprotective effect of the active fraction of Z. bungeanum.Results: We demonstrated that the mice treated with EA had significantly alleviated the memory deficit induced by D-galactose. Meanwhile, EA up-regulated the cortex NeuN protein level, improved the survival and morphology of hippocampal neurons. We further found that EA significantly alleviated oxidative damage, inhibited activation of microglia, and suppressed NLRP3 inflammasome activation and subsequent cleaved Caspase-1, IL-1β, IL-18, and GSDMD-N. Correspondingly, in vitro data showed that EA protected BV-2 cells against Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation and pyroptosis, evidenced by declined the protein levels of NLRP3, cleaved Caspase-1, IL-1β, IL-18, and GSDMD-N. These data indicated that EA inhibited NLRP3-mediated pyroptosis.Conclusions: Our work revealed that the EA active fraction of Z. bungeanum protected neurons from inflammation through inhibition of NLRP3 and subsequent pyroptosis in microglia, and suggested promising clinical use of EA for age-associated neurodegenerative disease.

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Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Cited by 64 publications

References 105 publications

Urokinase, CX3CL1, CCL2, TRAIL and IL‐18 induced by interferon‐β treatment

Urokinase, CX3CL1, CCL2, TRAIL and IL‐18 induced by interferon‐β treatment

Netosis and Inflammasomes in Large Vessel Occlusion Thrombi

Ethyl acetate extracts of Bungeanum ameliorates cognitive deficits by suppressing NLRP3 inflammasome-dependent pyroptosis in aging mice

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