Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine

Rothbard, Jonathan B.; Rothbard, Jesse J.; Soares, Luis; Fathman, C. Garrison; Steinman, Lawrence

doi:10.1073/pnas.1804599115

Cited by 22 publications

(17 citation statements)

References 41 publications

(58 reference statements)

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“…Previously, a study showed neuroprotection of nicotine from Aβ-induced neurotoxicity (Rothbard et al, 2018 ). Here, we examined nicotine effects on HT-22 cell viability after the application of H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through α7-nAChR/Erk1/2 Signaling Pathway

Dong

Zheng

et al. 2020

Front. Mol. Neurosci.

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Section: Resultsmentioning

confidence: 99%

Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through α7-nAChR/Erk1/2 Signaling Pathway

Dong

Zheng

et al. 2020

Front. Mol. Neurosci.

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“…5e-g). It is to be noted that other inflammatory modulators such as nicotine also suppresses EAE 40 . Nicotine mediated NFκB suppression involves down regulation of p65/p50 subunits of NFκB and blocking its binding to DNA 41 .…”

Section: Discussionmentioning

confidence: 99%

Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis

Vattathara

Prakash

Subhramanian

et al. 2020

Sci Rep

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The concept of substrate inhibition to prevent its phosphorylation has potential in drug discovery and is envisioned to treat the autoimmune disorder multiple sclerosis (MS). Glia maturation factor-β (GMF-β) Ser83 phosphorylation by protein kinase A (PKA) is pivotal in the activation of GMF-β-p38MAPK-NFκB biochemical pathway towards proinflammatory response induction in experimental autoimmune encephalomyelitis (EAE). Using structure-based drug design, we identified the small molecule inhibitor 1-H-indazole-4yl methanol (GMFBI.1) that specifically blocked Ser83 phosphorylation site on GMF-β substrate. Using in vitro and in vivo techniques, molecular mechanism of action of GMFBI.1's direct interaction with GMF-β substrate and prevention of its Ser83 phosphorylation was established. GMFBI.1 down regulated p38MAPK phosphorylation and NFκB expression essential for proinflammatory response. Further, GMFBI.1 administration at peak of EAE reversed clinical symptoms, immunopathology, proinflammatory cytokine response and up regulated the anti-inflammatory cytokines. Present strategy of substrate inhibition against the key immunomodulatory target has immense therapeutic potential in MS. Multiple sclerosis is a chronic autoimmune, demyelinating, neurodegenerative disorder of the central nervous system (CNS) affecting 2.5 million people globally 1,2. Despite different disease-modifying therapies adopted to mitigate the inflammatory milieu of MS using different drugs 3-5 , patient's progress from an acute phase to a stage with considerable neurological disabilities. Current therapies modulate disease differently as they target activated T cells, antigen presenting cells or prevent the egress of T cells into brain. Importantly, none of these drugs control molecules that modulate the proinflammatory response at a fundamental level following infiltration of activated T and B lymphocytes 6,7. Activated lymphocytes undergo clonal expansion assisted by the cytokines produced mainly by astrocytes and microglia and glia maturation factor-β (GMF-β) plays an instrumental role in cytokine induction 8,9. Thus, targeting GMF-β could signify a novel approach in controlling the immune response in the brain. Over expression of GMF-β in response to immune challenge up regulates p38MAPK and NFκB expression in astrocytes leading to increased GM-CSF production by astrocytes and microglial generation of TNF-α, IL1-β, IL-6 and IFN-γ, augmenting proinflammatory response 10-12. In the well-established EAE animal model of MS,

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“…34 A group in France proposed a potential role of nicotine as the agent responsible for smoking's action on the ACE2 receptor, potentially providing a protective mechanism for smoking in COVID-19. Nicotine is also of interest because it could help in COVID-19 by mitigating a host of destructive inflammatory reactions 35,36 that often are associated with deterioration in the later stages of COVID-19. 37,38 Another mechanism of interest is nitric oxide (NO) which is one of the many chemicals found in cigarette smoke, and also relevant to nicotine.…”

Section: Discussionmentioning

confidence: 99%

National Smoking Rates Correlate Inversely with COVID-19 Mortality

Norden¹,

Avery

Norden

et al. 2020

Preprint

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IntroductionRecent studies show cigarette smokers are markedly under-represented among patients hospitalized for COVID-19 in over a dozen countries. It is unclear if this may be related to confounding factors such as age distribution, access to care, and inaccurate records. We hypothesized that these concerns could be avoided by studying smoking prevalence in relation to COVID-19 mortality. Since climate has been identified as a factor in COVID-19, we studied groups of countries with relatively comparable temperatures.MethodsThe 20 hottest and 20 coldest countries in the Johns Hopkins Mortality Analysis database with a minimum mortality rate of .3 deaths/100,000 were selected on the basis of the average temperatures of their largest city. Mortality rates were determined as of May 1, 2020 and correlated with national smoking rate adjusting for sex ratio, obesity, temperature, and elderly population.ResultsA highly significant inverse correlation between current daily smoking prevalence and COVID-19 mortality rate was noted for the group of hot countries (R=-.718, p = .0002), cold countries (R=-.567, p=.0046), and the combined group (R=-.324, p=.0207). However, after adjustments only the regression for hot countries and the combined group remained significant. In hot countries, for each percentage point increase in smoking rate mortality decreased by .147 per 100,000 population (95% CI .102-192, p=.0066). This resulted in mortality rates several-fold elevated in the countries with the lowest smoking rates relative to the highest smoking rates. In the combined group, mortality decreased by .257 per 100,000 population (95% CI .175-.339, p=.0034).DiscussionThese findings add support to the finding of an inverse relationship between current smoking and seriously symptomatic COVID-19. However, we conclude that the difference in mortality between the highest and lowest smoking countries appears too large to be due primarily to the effects of smoking per se. A potentially beneficial effect of smoking is surprising, but compatible with a number of hypothetical mechanisms which deserve exploration: 1) Studies show smoking alters ACE2 expression which may affect COVID-19 infection or its progression to serious lung pathology. 2) Nicotine has anti-inflammatory activity and also appears to alter ACE2 expression. 3) Nitric oxide in cigarette smoke is known to be effective in treating pulmonary hypertension and has shown in vitro antiviral effects including against SARS-CoV-2. 4) Smoking has complicated effects on the immune system involving both up and down regulation, any of which might alone or in concert antagonize progression of COVID-19. 5) Smokers are exposed to hot vapors which may stimulate immunity in the respiratory tract by various heat-related mechanisms (e.g. heat shock proteins). Studies of steam and sauna treatments have shown efficacy in other viral respiratory conditions. At this time there is no clear evidence that smoking is protective against COVID-19, so the established recommendations to avoid smoking should be emphasized. The interaction of smoking and COVID-19 will only be reliably determined by carefully designed prospective study, and there is reason to believe that there are unknown confounds that may be spuriously suggesting a protective effect of smoking. However, the magnitude of the apparent inverse association of COVID-19 and smoking and its myriad clinical implications suggest the importance of further investigation.

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Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine

Cited by 22 publications

References 41 publications

Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through α7-nAChR/Erk1/2 Signaling Pathway

Nicotine Prevents Oxidative Stress-Induced Hippocampal Neuronal Injury Through α7-nAChR/Erk1/2 Signaling Pathway

Substrate Specific Inhibitor Designed against the Immunomodulator GMF-beta Reversed the Experimental Autoimmune Encephalomyelitis

National Smoking Rates Correlate Inversely with COVID-19 Mortality

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