The critical role of the hippocampal NLRP3 inflammasome in social isolation-induced cognitive impairment in male mice

Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.

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The role of inflammasomes in vascular cognitive impairment

Molecular Neurodegeneration ◽

10.1186/s13024-021-00506-8 ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

Luting Poh ◽

Wei Liang Sim ◽

Dong-Gyu Jo ◽

Quynh Nhu Dinh ◽

Grant R. Drummond ◽

...

Keyword(s):

Cognitive Impairment ◽

Critical Role ◽

Disease Onset ◽

The Elderly ◽

Vascular Cognitive Impairment ◽

Cerebral Hypoperfusion ◽

Early Event ◽

Cellular Mechanisms ◽

Structural Brain Damage

AbstractThere is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

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The possible role of nitric oxide in anti-convulsant effects of Naltrindole in seizure-induced by social isolation stress in male mice

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110453 ◽

2020 ◽

Vol 129 ◽

pp. 110453 ◽

Cited By ~ 1

Author(s):

Rajan Nikbakhsh ◽

Rambod Nikbakhsh ◽

Mahla Radmard ◽

Armin Tafazolimoghadam ◽

Arvin Haj-Mirzaian ◽

...

Keyword(s):

Nitric Oxide ◽

Social Isolation ◽

Male Mice ◽

Isolation Stress ◽

Social Isolation Stress

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NLRP3 inflammasome is involved in uterine activation for labor at term and preterm

Reproduction ◽

10.1530/rep-21-0047 ◽

2021 ◽

Vol 162 (6) ◽

pp. 449-460

Author(s):

Zixi Chen ◽

Yali Shan ◽

Xingji You ◽

Hang Gu ◽

Chen Xu ◽

...

Keyword(s):

Mouse Model ◽

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Critical Role ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Pregnant Mice ◽

Labor Onset

The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases. We sought to investigate the role of NLRP3 inflammasome in uterine activation for labor at term and preterm. We found that NLRP3 inflammasome was activated in the myometrium tissues obtained from the pregnant women undergoing labor at term (TL) compared with those not undergoing labor (TNL) at term. NLRP3 inflammasome was also activated in amnion and chorion-deciduas in TL and preterm labor (PTL) groups. In the mouse model, uterine NLRP3 inflammasome and nuclear factor kappaB (NF-κB) were activated toward term and during labor. Treatment of pregnant mice with lipopolysaccharide (LPS) and RU38486 induced preterm birth (PTB) and also promoted uterine NLRP3 inflammasome and NF-κB activation. Treatment of pregnant mice with NLRP3 inflammasome inhibitor BAY11-7082 and MCC950 delayed the onset of labor and suppressed NLRP3 inflammasome and NF-κB activation in uterus. MCC950 postponed labor onset of the mice with LPS and RU38486 treatment and inhibited NLRP3 inflammasome activation in uterus. Our data provide the evidence that NLRP3 inflammasome is involved in uterine activation for labor onset in term and PTB in humans and mouse model.

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Critical Role of Endoplasmic Reticulum Stress in Cognitive Impairment Induced by Microcystin-LR

International Journal of Molecular Sciences ◽

10.3390/ijms161226083 ◽

2015 ◽

Vol 16 (12) ◽

pp. 28077-28086 ◽

Cited By ~ 21

Author(s):

Fei Cai ◽

Jue Liu ◽

Cairong Li ◽

Jianghua Wang

Keyword(s):

Endoplasmic Reticulum ◽

Cognitive Impairment ◽

Endoplasmic Reticulum Stress ◽

Critical Role

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NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

Viruses ◽

10.3390/v13040692 ◽

2021 ◽

Vol 13 (4) ◽

pp. 692

Author(s):

Carrie-Anne Malinczak ◽

Charles F. Schuler ◽

Angela J. Duran ◽

Andrew J. Rasky ◽

Mohamed M. Mire ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Severe Disease ◽

Critical Role ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Increased Risk ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3−/−) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

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Sustaining prospective memory functioning in amnestic mild cognitive impairment: A lifespan approach to the critical role of encoding.

Neuropsychology ◽

10.1037/neu0000441 ◽

2018 ◽

Vol 32 (5) ◽

pp. 634-644 ◽

Cited By ~ 1

Author(s):

Antonina Pereira ◽

Mareike Altgassen ◽

Lesley Atchison ◽

Alexandre de Mendonça ◽

Judi Ellis

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Prospective Memory ◽

Critical Role ◽

Amnestic Mild Cognitive Impairment ◽

Memory Functioning

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Cognitive health risks posed by social isolation and loneliness in older Korean Americans

BMC Geriatrics ◽

10.1186/s12877-021-02066-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yuri Jang ◽

Eun Young Choi ◽

Nan Sook Park ◽

David A. Chiriboga ◽

Lei Duan ◽

...

Keyword(s):

Cognitive Impairment ◽

Social Isolation ◽

Health Risks ◽

Korean Americans ◽

Cognitive Health ◽

Subjective Cognitive Impairment ◽

Mediating Role ◽

The Relationship ◽

Older Korean Americans

Abstract Background This study examines associations among social isolation, loneliness, and cognitive health risks in older Korean Americans, focusing on the mediating role of loneliness in the relationship between social isolation and objective and subjective measures of cognitive impairment. Methods Data are from 2061 participants in the Study of Older Korean Americans, a multi-state survey of Korean immigrants age 60 and older (Mage = 73.2, SD = 7.93). Social isolation was indexed with the Lubben Social Network Scale− 6; loneliness, with the short-form UCLA Loneliness Scale. Objective and subjective measures of cognitive impairment included the Mini-Mental State Examination and a single-item self-rating of cognitive health. Results In the logistic regression model for objective cognitive impairment, social isolation was significantly associated, but loneliness was not. In the model for subjective cognitive impairment, both social isolation and loneliness were significant factors. However, the effect of social isolation became non-significant when loneliness was considered, suggesting a potential mediating role of loneliness. The subsequent mediation analysis confirmed that the indirect effect of social isolation on subjective cognitive impairment through loneliness was significant (B = .20, SE = .03, 95% CI = .12, .28). Conclusion Our analyses provide evidence for the proposed mediating effect of loneliness in the relationship between social isolation and subjective cognitive impairment. Intervention efforts should focus on reducing feelings of loneliness experienced by older immigrants, possibly by engaging them in socially meaningful and cognitively stimulating activities.

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Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages

Cells ◽

10.3390/cells9081753 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1753 ◽

Cited By ~ 1

Author(s):

Bhakta Prasad Gaire ◽

Chi-Ho Lee ◽

Wondong Kim ◽

Arjun Sapkota ◽

Do Yup Lee ◽

...

Keyword(s):

Lysophosphatidic Acid ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Skin Barrier ◽

Underlying Mechanism ◽

Inflammasome Activation ◽

Lpa Receptor ◽

Nlrp3 Inflammasome Activation ◽

Injured Skin

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1β maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.

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