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Open Access 01-12-2021 | Heat Stroke | Research

NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1β-mediated neuroinflammation

Authors: Zi-Teng Zhang, Xiao-Lei Gu, Xin Zhao, Xian He, Hao-Wei Shi, Kun Zhang, Yi-Ming Zhang, Yi-Nan Su, Jiang-Bo Zhu, Zhi-Wei Li, Guo-Bao Li

Published in: Journal of Neuroinflammation | Issue 1/2021

Abstract

Background

Patients with prior illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke.

Methods

In this study, we used a classic animal heat stroke model. Prior infection was mimicked by using lipopolysaccharide (LPS) or lipoteichoic acid (LTA) injection before heat stroke (LPS/LTA 1 mg/kg). Mice survival analysis curve and core temperature (T_C) elevation curve were produced. NLRP3 inflammasome activation was measured by using real-time PCR and Western blot. Mice hypothalamus was dissected and neuroinflammation level was measured. To further demonstrate the role of NLRP3 inflammasome, Nlrp3 knockout mice were used. In addition, IL-1β neutralizing antibody was injected to test potential therapeutic effect on heat stroke.

Results

Prior infection simulated by LPS/LTA injection resulted in latent inflammation status presented by high levels of cytokines in peripheral serum. However, LPS/LTA failed to cause any change in animal survival rate or body temperature. In the absence of LPS/LTA, heat treatment induced heat stroke and animal death without significant systemic or neuroinflammation. Despite a decreased level of IL-1β in hypothalamus, Nlrp3 knockout mice demonstrated no survival advantage under mere heat exposure. In animals with prior infection, their heat tolerance was severely impaired and NLRP3 inflammasome induced neuroinflammation was detected. The use of Nlrp3 knockout mice enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1β production with prior infection condition. Furthermore, IL-1β neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke.

Conclusions

Based on the above results, NLRP3/IL-1β induced neuroinflammation might be an important mechanistic factor in heat stroke pathology, especially with prior infection. IL-1β may serve as a biomarker for heat stroke severity and potential therapeutic method.

Cheshire WP Jr. Thermoregulatory disorders and illness related to heat and cold stress. Auton Neurosci. 2016;196:91–104. https://doi.org/10.1016/j.autneu.2016.01.001.CrossRefPubMed

Chang CY, Chen JY, Chen SH, Cheng TJ, Lin MT, Hu ML. Therapeutic treatment with ascorbate rescues mice from heat stroke-induced death by attenuating systemic inflammatory response and hypothalamic neuronal damage. Free Radic Biol Med. 2016;93:84–93. https://doi.org/10.1016/j.freeradbiomed.2015.12.017.CrossRefPubMed

Peiris AN, Jaroudi S, Noor R. Heat stroke. JAMA. 2017;318(24):2503. https://doi.org/10.1001/jama.2017.18780.CrossRefPubMed

Armstrong LE, Lee EC, Armstrong EM. Interactions of gut microbiota, endotoxemia, immune function, and diet in exertional heatstroke. J Sports Med (Hindawi Publ Corp). 2018;2018:5724575.

King MA, Ward MD, Mayer TA, Plamper ML, Madsen CM, Cheuvront SN, et al. Influence of prior illness on exertional heat stroke presentation and outcome. Plos One. 2019;14(8):e0221329. https://doi.org/10.1371/journal.pone.0221329.CrossRefPubMedPubMedCentral

Westwood CS, Fallowfield JL, Delves SK, Nunns M, Ogden HB, Layden JD. Individual risk factors associated with exertional heat illness: a systematic review. Exp Physiol. 2021;106(1):191–9. https://doi.org/10.1113/EP088458.CrossRefPubMed

Liu CC, Shih MF, Wen YS, Lai YH, Yang TH. Dexamethasone improves heat stroke-induced multiorgan dysfunction and damage in rats. Int J Mol Sci. 2014;15(11):21299–313. https://doi.org/10.3390/ijms151121299.CrossRefPubMedPubMedCentral

Dematte JE, O'Mara K, Buescher J, Whitney CG, Forsythe S, McNamee T, et al. Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med. 1998;129(3):173–81. https://doi.org/10.7326/0003-4819-129-3-199808010-00001.CrossRefPubMed

Morrison SF. Central control of body temperature. F1000Res. 2016;5:F1000 Faculty Rev-880. https://doi.org/10.12688/f1000research.7958.1.

10.

Morrison SF, Nakamura K. Central mechanisms for thermoregulation. Annu Rev Physiol. 2019;81(1):285–308. https://doi.org/10.1146/annurev-physiol-020518-114546.CrossRefPubMed

11.

Smith CJ, Johnson JM. Responses to hyperthermia. Optimizing heat dissipation by convection and evaporation: neural control of skin blood flow and sweating in humans. Auton Neurosci. 2016;196:25–36. https://doi.org/10.1016/j.autneu.2016.01.002.CrossRefPubMed

12.

Tan CL, Knight ZA. Regulation of body temperature by the nervous system. Neuron. 2018;98(1):31–48. https://doi.org/10.1016/j.neuron.2018.02.022.CrossRefPubMedPubMedCentral

13.

Lin XJ, Li YJ, Li ZL, Zou F, Lin MT. Pre-existing lipopolysaccharide may increase the risk of heatstroke in rats. Am J Med Sci. 2009;337(4):265–70. https://doi.org/10.1097/MAJ.0b013e31818b0fa2.CrossRefPubMed

14.

Lim CL. Heat sepsis precedes heat toxicity in the pathophysiology of heat stroke-A new paradigm on an ancient disease. Antioxidants (Basel). 2018;7(11):149. https://doi.org/10.3390/antiox7110149.

15.

Helwig BG, Leon LR. Tissue and circulating expression of IL-1 family members following heat stroke. Physiol Genomics. 2011;43(19):1096–104. https://doi.org/10.1152/physiolgenomics.00076.2011.CrossRefPubMed

16.

Hammami MM, Bouchama A, Al-Sedairy S, Shail E, AlOhaly Y, Mohamed GE. Concentrations of soluble tumor necrosis factor and interleukin-6 receptors in heatstroke and heatstress. Crit Care Med. 1997;25(8):1314–9. https://doi.org/10.1097/00003246-199708000-00017.CrossRefPubMed

17.

Geng Y, Ma Q, Liu YN, Peng N, Yuan FF, Li XG, et al. Heatstroke induces liver injury via IL-1beta and HMGB1-induced pyroptosis. J Hepatol. 2015;63(3):622–33. https://doi.org/10.1016/j.jhep.2015.04.010.CrossRefPubMed

18.

Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210–5. https://doi.org/10.1038/nri2725.CrossRefPubMed

19.

Zhang ZT, Du XM, Ma XJ, Zong Y, Chen JK, Yu CL, et al. Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome. J Neuroinflammation. 2016;13(1):71. https://doi.org/10.1186/s12974-016-0539-1.CrossRefPubMedPubMedCentral

20.

Hsu SF, Niu KC, Lin CL, Lin MT. Brain cooling causes attenuation of cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke. Shock. 2006;26(2):210–20. https://doi.org/10.1097/01.shk.0000223124.49265.10.CrossRefPubMed

21.

McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985;109(8):716–21.PubMed

22.

Hamilton CL, Ciaccia PJ. Hypothalamus, temperature regulation, and feeding in the rat. Am J Physiol. 1971;221(3):800–7. https://doi.org/10.1152/ajplegacy.1971.221.3.800.CrossRefPubMed

23.

Albukrek D, Bakon M, Moran DS, Faibel M, Epstein Y. Heat-stroke-induced cerebellar atrophy: clinical course, CT and MRI findings. Neuroradiology. 1997;39(3):195–7. https://doi.org/10.1007/s002340050392.CrossRefPubMed

24.

Huai W, Zhao R, Song H, Zhao J, Zhang L, Zhang L, et al. Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription. Nat Commun. 2014;5(1):4738. https://doi.org/10.1038/ncomms5738.CrossRefPubMed

25.

White-Newsome JL, Ekwurzel B, Baer-Schultz M, Ebi KL, O'Neill MS, Anderson GB. Survey of county-level heat preparedness and response to the 2011 summer heat in 30 U.S. States. Environ Health Perspect. 2014;122(6):573–9. https://doi.org/10.1289/ehp.1306693.CrossRefPubMedPubMedCentral

26.

Wang Y, Bobb JF, Papi B, Wang Y, Kosheleva A, Di Q, et al. Heat stroke admissions during heat waves in 1,916 US counties for the period from 1999 to 2010 and their effect modifiers. Environ Health. 2016;15(1):83. https://doi.org/10.1186/s12940-016-0167-3.CrossRefPubMedPubMedCentral

27.

Hopp S, Dominici F, Bobb JF. Medical diagnoses of heat wave-related hospital admissions in older adults. Prev Med. 2018;110:81–5. https://doi.org/10.1016/j.ypmed.2018.02.001.CrossRefPubMedPubMedCentral

28.

Hashim IA. Clinical biochemistry of hyperthermia. Ann Clin Biochem. 2010;47(6):516–23. https://doi.org/10.1258/acb.2010.010186.CrossRefPubMed

29.

Xia ZN, Zong Y, Zhang ZT, Chen JK, Ma XJ, Liu YG, et al. Dexmedetomidine protects against multi-organ dysfunction induced by heatstroke via sustaining the intestinal integrity. Shock. 2017;48(2):260–9. https://doi.org/10.1097/SHK.0000000000000826.CrossRefPubMed

30.

Armstrong LE, Lee EC, Armstrong EM. Interactions of gut microbiota, endotoxemia, immune function, and diet in exertional heatstroke. J Sports Med. 2018;2018:1–33. https://doi.org/10.1155/2018/5724575.CrossRef

31.

Bouchama A, Knochel JP. Heat stroke. N Engl J Med. 2002;346(25):1978–88. https://doi.org/10.1056/NEJMra011089.CrossRefPubMed

32.

Phillips NA, Welc SS, Wallet SM, King MA, Clanton TL. Protection of intestinal injury during heat stroke in mice by interleukin-6 pretreatment. J Physiol. 2015;593(3):739–52; discussion 753. https://doi.org/10.1113/jphysiol.2014.283416.CrossRefPubMedPubMedCentral

33.

Proctor EA, Dineen SM, Van Nostrand SC, Kuhn MK, Barrett CD, Brubaker DK, et al. Coagulopathy signature precedes and predicts severity of end-organ heat stroke pathology in a mouse model. J Thromb Haemost. 2020;18(8):1900–10. https://doi.org/10.1111/jth.14875.CrossRefPubMedPubMedCentral

34.

Dineen SM, Ward JA, Leon LR. Prior viral illness increases heat stroke severity in mice. Exp Physiol. 2021;106(1):244–57. https://doi.org/10.1113/EP088480.CrossRefPubMed

35.

Ahn H, Kim J, Jeung EB, Lee GS. Dimethyl sulfoxide inhibits NLRP3 inflammasome activation. Immunobiology. 2014;219(4):315–22. https://doi.org/10.1016/j.imbio.2013.11.003.CrossRefPubMed

36.

Del Vesco AP, Gasparino E. Production of reactive oxygen species, gene expression, and enzymatic activity in quail subjected to acute heat stress. J Anim Sci. 2013;91(2):582–7. https://doi.org/10.2527/jas.2012-5498.CrossRefPubMed

37.

Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52. https://doi.org/10.1038/nrd3800.CrossRefPubMedPubMedCentral

38.

Alcocer-Gomez E, Ulecia-Moron C, Marin-Aguilar F, Rybkina T, Casas-Barquero N, Ruiz-Cabello J, et al. Stress-induced depressive behaviors require a functional NLRP3 inflammasome. Mol Neurobiol. 2016;53(7):4874–82. https://doi.org/10.1007/s12035-015-9408-7.CrossRefPubMed

39.

Sepehri Z, Kiani Z, Afshari M, Kohan F, Dalvand A, Ghavami S. Inflammasomes and type 2 diabetes: an updated systematic review. Immunol Lett. 2017;192:97–103. https://doi.org/10.1016/j.imlet.2017.10.010.CrossRefPubMed

40.

Lee S, Suh GY, Ryter SW, Choi AM. Regulation and function of the nucleotide binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 inflammasome in lung disease. Am J Respir Cell Mol Biol. 2016;54(2):151–60. https://doi.org/10.1165/rcmb.2015-0231TR.CrossRefPubMedPubMedCentral

41.

Liu YG, Chen JK, Zhang ZT, Ma XJ, Chen YC, Du XM, et al. NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages. Cell Death Dis. 2017;8(2):e2579. https://doi.org/10.1038/cddis.2016.460.CrossRefPubMedPubMedCentral

Title: NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1β-mediated neuroinflammation
Authors: Zi-Teng Zhang
Xiao-Lei Gu
Xin Zhao
Xian He
Hao-Wei Shi
Kun Zhang
Yi-Ming Zhang
Yi-Nan Su
Jiang-Bo Zhu
Zhi-Wei Li
Guo-Bao Li
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Heat Stroke
Pathology
Heat Stroke
Published in: Journal of Neuroinflammation / Issue 1/2021
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-021-02179-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1β-mediated neuroinflammation

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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