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Regulation of Inflammation by IRAK-M Pathway Can Be Associated with nAchRalpha7 Activation and COVID-19

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Abstract

In spite of the vaccine development and its importance, the SARS-CoV-2 pandemic is still impacting the world. It is known that the COVID-19 severity is related to the cytokine storm phenomenon, being inflammation a common disease feature. The nicotinic cholinergic system has been widely associated with COVID-19 since it plays a protective role in inflammation via nicotinic receptor alpha 7 (nAchRalpha7). In addition, SARS-CoV-2 spike protein (Spro) subunits can interact with nAchRalpha7. Moreover, Spro causes toll-like receptor (TLR) activation, leading to pro- and anti-inflammatory pathways. The increase and maturation of the IL-1 receptor-associated kinase (IRAK) family are mediated by activation of membrane receptors, such as TLRs. IRAK-M, a member of this family, is responsible for negatively regulating the activity of other active IRAKs. In addition, IRAK-M can regulate microglia phenotype by specific protein expression. Furthermore, there exists an antagonist influence of SARS-CoV-2 Spro and the cholinergic system action on the IRAK-M pathway and microglia phenotype. We discuss the overexpression and suppression of IRAK-M in inflammatory cell response to inflammation in SARS-CoV-2 infection when the cholinergic system is constantly activated via nAchRalpha7.

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References

  1. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, Xing F, Liu J et al (2020) A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 395:514–523. https://doi.org/10.1016/S0140-6736(20)30154-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kobayashi K, Hernandez LD, Galán JE, Janeway CA Jr, Medzhitov R, Flavell RA (2002a) IRAK-M is a negative regulator of toll-like receptor signaling. Cell 110:191–202

    Article  CAS  PubMed  Google Scholar 

  3. Aghagoli G, Gallo Marin B, Katchur NJ, Chaves-Sell F, Asaad WF, Murphy SA (2021) Neurological involvement in COVID-19 and potential mechanisms: a review. Neurocrit Care 34:1062–1071. https://doi.org/10.1007/s12028-020-01049-4

    Article  CAS  PubMed  Google Scholar 

  4. Murta V, Villarreal A, Ramos AJ (2020) Severe acute respiratory syndrome coronavirus 2 impact on the central nervous system: are astrocytes and microglia main players or merely bystanders? ASN Neuro 12:1759091420954960. https://doi.org/10.1177/1759091420954960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alam SB, Willows S, Kulka M, Sandhu JK (2020) Severe acute respiratory syndrome coronavirus 2 may be an underappreciated pathogen of the central nervous system. Eur J Neurol 27:2348–2360. https://doi.org/10.1111/ene.14442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Solomon T (2021) Neurological infection with SARS-CoV-2 — the story so far. Nat Rev Neurol 17:65–66. https://doi.org/10.1038/s41582-020-00453-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pajo AT, Espiritu AI, Apor ADAO, Jamora RDG (2021) Neuropathologic findings of patients with COVID-19: a systematic review. Neurol Sci 42:1255–1266. https://doi.org/10.1007/s10072-021-05068-7

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yang F, Shi S, Zhu J, Shi J, Dai K, Chen X (2020) Analysis of 92 deceased patients with COVID-19. J Med Virol 92:2511–2515. https://doi.org/10.1002/jmv.25891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, Dequanter D, Blecic S et al (2020) Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Oto-Rhino-Laryngology 277:2251–2261. https://doi.org/10.1007/s00405-020-05965-1

    Article  Google Scholar 

  10. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C et al (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 77:683–690. https://doi.org/10.1001/jamaneurol.2020.1127

    Article  PubMed  Google Scholar 

  11. Stefano GB, Büttiker P, Weissenberger S, Martin A, Ptacek R, Kream RM (2021) Editorial: The pathogenesis of long-term neuropsychiatric covid-19 and the role of microglia, mitochondria, and persistent neuroinflammation: a hypothesis. Med Sci Monit 27:1–4. https://doi.org/10.12659/MSM.933015

    Article  Google Scholar 

  12. Baig AM (2021a) Chronic long-COVID syndrome: a protracted COVID-19 illness with neurological dysfunctions. CNS Neurosci Ther 27:1433–1436. https://doi.org/10.1111/cns.13737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Baig AM (2021b) Chronic COVID syndrome: need for an appropriate medical terminology for long-COVID and COVID long-haulers. J Med Virol 93:2555–2556. https://doi.org/10.1002/jmv.26624

    Article  CAS  PubMed  Google Scholar 

  14. Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, Sakata H et al (2020) A first case of meningitis / encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis 94:55–58. https://doi.org/10.1016/j.ijid.2020.03.062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M (2020) Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol 92(7):699–702. https://doi.org/10.1002/jmv.25915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Baig AM, Khaleeq A, Ali U, Syeda H (2020a) Evidence of the COVID-19 virus targeting the CNS: tissue distribution, hostvirus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 11:995–998. https://doi.org/10.1021/acschemneuro.0c00122

    Article  CAS  PubMed  Google Scholar 

  17. Jiao L, Yang Y, Yu W, Zhao Y, Long H, Gao J, Ding K, Ma C et al (2021) The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys. Signal Transduct Target Ther 6:169. https://doi.org/10.1038/s41392-021-00591-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dubé M, Le Coupanec A, AHM W, Rini JM, Desforges M, Talbot PJ (2018) Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43. J Virol 92. https://doi.org/10.1128/JVI.00404-18

  19. Mishra R, Banerjea AC (2021) SARS-CoV-2 spike targets USP33-IRF9 axis via exosomal miR-148a to activate human microglia. Front Immunol 12:1–16. https://doi.org/10.3389/fimmu.2021.656700

    Article  CAS  Google Scholar 

  20. Wu J, Tang Y (2020) Revisiting the immune balance theory: a neurological insight into the epidemic of COVID-19 and ITS ALIke. Front Neurol 11:566680. https://doi.org/10.3389/fneur.2020.566680

  21. Ludlow M, Kortekaas J, Herden C, Hoffmann B (2016) Neurotropic virus infections as the cause of immediate and delayed neuropathology. Acta Neuropathol 131:159–184. https://doi.org/10.1007/s00401-015-1511-3

    Article  CAS  PubMed  Google Scholar 

  22. Bryche B, St Albin A, Murri S, Lacôte S, Pulido C, Ar Gouilh M, Lesellier S, Servat A et al (2020) Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters. Brain Behav Immun 89:579–586. https://doi.org/10.1016/j.bbi.2020.06.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fodoulian L, Tuberosa J, Rossier D, Boillat M, Kan C, Pauli V, Egervari K, Lobrinus JA et al (2020) SARS-CoV-2 receptors and entry genes are expressed in the human olfactory neuroepithelium and brain. iScience 23(12):101839. https://doi.org/10.1016/j.isci.2020.101839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Matsuda K, Park CH, Sunden Y, Kimura T, Ochiai K, Kida H, Umemura T (2004) The vagus nerve is one route of transneural invasion for intranasally inoculated influenza A virus in mice. Vet Pathol 41:101–107. https://doi.org/10.1354/vp.41-2-101

    Article  CAS  PubMed  Google Scholar 

  25. Breit S, Kupferberg A, Rogler G, Hasler G (2018) Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front Psychiatry 9(44):13. https://doi.org/10.3389/fpsyt.2018.00044

    Article  Google Scholar 

  26. Chen L, Li X, Chen M, Feng Y, Xiong C (2020) The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 116(6):1097–1100. https://doi.org/10.1093/cvr/cvaa078

    Article  CAS  PubMed  Google Scholar 

  27. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 395:497–506. https://doi.org/10.1016/S0140-6736(20)30183-5

    Article  CAS  PubMed  Google Scholar 

  28. Hosseini A, Hashemi V, Shomali N, Asghari F, Gharibi T, Akbari M, Gholizadeh S, Jafari A (2020) Innate and adaptive immune responses against coronavirus. Biomed Pharmacother 132:110859. https://doi.org/10.1016/j.biopha.2020.110859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9:429–439. https://doi.org/10.1038/nri2565

    Article  CAS  PubMed  Google Scholar 

  30. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–145. https://doi.org/10.1016/j.it.2007.01.005

    Article  CAS  PubMed  Google Scholar 

  31. Li F, Wang Y, Yu L, Cao S, Wang K, Yuan J, Wang C, Wang K et al (2015) Viral infection of the central nervous system and neuroinflammation precede blood-brain barrier disruption during Japanese encephalitis virus infection. J Virol 89:5602–5614. https://doi.org/10.1128/jvi.00143-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Begley DJ, Brightman MW (2003) Structural and functional aspects of the blood-brain barrier. Prog drug Res Fortschritte der Arzneimittelforschung Prog des Rech Pharm 61:39–78. https://doi.org/10.1007/978-3-0348-8049-7_2

    Article  CAS  Google Scholar 

  33. Abbott NJ (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:629–638. https://doi.org/10.1046/j.1469-7580.2002.00064.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pardridge WM (1999) Blood-brain barrier biology and methodology. J Neurovirol 5:556–569. https://doi.org/10.3109/13550289909021285

    Article  CAS  PubMed  Google Scholar 

  35. McGonagle D, Sharif K, O’Regan A, Bridgewood C (2020) The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 19(6):102537. https://doi.org/10.1016/j.autrev.2020.102537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167. https://doi.org/10.1038/nri2015

    Article  CAS  PubMed  Google Scholar 

  37. Boroujeni ME, Simani L, Bluyssen HAR, Samadikhah HR, Zamanlui Benisi S, Hassani S, Akbari Dilmaghani N, Fathi M et al (2021) Inflammatory response leads to neuronal death in human post-mortem cerebral cortex in patients with COVID-19. ACS Chem Neurosci 12:2143–2150. https://doi.org/10.1021/acschemneuro.1c00111

    Article  CAS  PubMed  Google Scholar 

  38. Liu Q, Ding JL (2016) The molecular mechanisms of TLR-signaling cooperation in cytokine regulation. Immunol Cell Biol 94:538–542. https://doi.org/10.1038/icb.2016.18

    Article  CAS  PubMed  Google Scholar 

  39. Courties A, Boussier J, Hadjadj J, Yatim N, Barnabei L, Péré H, Veyer D, Kernéis S et al (2021) Regulation of the acetylcholine/α7nAChR anti-inflammatory pathway in COVID-19 patients. Sci Rep 11:1–8. https://doi.org/10.1038/s41598-021-91417-7

    Article  CAS  Google Scholar 

  40. Tizabi Y, Getachew B, Copeland RL, Aschner M (2020) Nicotine and the nicotinic cholinergic system in COVID-19. FEBS J 287:3656–3663. https://doi.org/10.1111/febs.15521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Farsalinos K, Niaura R, Le Houezec J, Barbouni A, Tsatsakis A, Kouretas D, Vantarakis A, Poulas K (2020a) Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system. Toxicol Reports 7:658–663. https://doi.org/10.1016/j.toxrep.2020.04.012

    Article  CAS  Google Scholar 

  42. Bonaz BL, Bernstein CN (2013) Brain-gut interactions in inflammatory bowel disease. Gastroenterology 144:36–49. https://doi.org/10.1053/j.gastro.2012.10.003

    Article  PubMed  Google Scholar 

  43. Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Investig 117(2):289–296. https://doi.org/10.1172/JCI30555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bonaz B, Sinniger V, Pellissier S (2016) Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol 594:5781–5790. https://doi.org/10.1113/JP271539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rakhi NN, Biswas R (2021) Smoking enigma in coronavirus disease 2019: a tug of war between predisposition and possible way out. Tob Use Insights 14:1179173x2098867. https://doi.org/10.1177/1179173x20988674

    Article  Google Scholar 

  46. Farsalinos K, Barbouni A, Niaura R (2020b) Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option? Intern Emerg Med 15:845–852. https://doi.org/10.1007/s11739-020-02355-7

    Article  PubMed  PubMed Central  Google Scholar 

  47. Li Q, Zhou X-D, Kolosov VP, Perelman JM (2011a) Cellular physiology and biochemistry biochemistry nicotine reduces TNF- α expression through a α 7 nAChR / MyD88 / NF- κ B pathway in HBE16 air. Cell Physiol Biochem 27:605–612

    Article  PubMed  Google Scholar 

  48. Li Q, Zhou X-D, Kolosov VP, Perelman JM (2011b) Nicotine reduces TNF-α expression through a α7 nAChR/MyD88/NF-ĸB pathway in HBE16 airway epithelial cells. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 27:605–612. https://doi.org/10.1159/000329982

    Article  CAS  Google Scholar 

  49. Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ (2023) Dopamine, immunity, and disease. Pharmacol Rev 75:62–158. https://doi.org/10.1124/pharmrev.122.000618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sriram K, Insel MB, Insel PA (2021) Inhaled β2 adrenergic agonists and other cAMP-elevating agents: therapeutics for alveolar injury and acute respiratory disease syndrome? Pharmacol Rev 73:488–526. https://doi.org/10.1124/pharmrev.121.000356

    Article  PubMed  Google Scholar 

  51. Rosen B, Kurtishi A, Vazquez-Jimenez GR, Møller SG (2021) The intersection of Parkinson’s disease, viral infections, and COVID-19. Mol Neurobiol 58:4477–4486. https://doi.org/10.1007/s12035-021-02408-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dienel A, Veettil RA, Matsumura K et al (2021) α7-Acetylcholine receptor signaling reduces neuroinflammation after subarachnoid hemorrhage in mice. Neurotherapeutics. https://doi.org/10.1007/s13311-021-01052-3

  53. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H et al (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388. https://doi.org/10.1038/nature01339

    Article  CAS  PubMed  Google Scholar 

  54. Sun P, Liu DG, Ye XM (2021) Nicotinic acetylcholine receptor α7 subunit is an essential regulator of seizure susceptibility. Front Neurol 12:1–5. https://doi.org/10.3389/fneur.2021.656752

    Article  Google Scholar 

  55. Farsalinos K, Eliopoulos E, Leonidas DD, Papadopoulos GE, Tzartos S, Poulas K (2020c) Nicotinic cholinergic system and covid-19: in silico identification of an interaction between sars-cov-2 and nicotinic receptors with potential therapeutic targeting implications. Int J Mol Sci 21:1–15. https://doi.org/10.3390/ijms21165807

    Article  CAS  Google Scholar 

  56. Alexandris N, Lagoumintzis G, Chasapis CT, Leonidas DD, Papadopoulos GE, Tzartos SJ, Tsatsakis A, Eliopoulos E et al (2021) Nicotinic cholinergic system and COVID-19: in silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions. Toxicol Reports 8:73–83. https://doi.org/10.1016/j.toxrep.2020.12.013

    Article  CAS  Google Scholar 

  57. Lagoumintzis G, Chasapis CT, Alexandris N, Kouretas D, Tzartos S, Eliopoulos E, Farsalinos K, Poulas K (2021) Nicotinic cholinergic system and COVID-19: in silico identification of interactions between α7 nicotinic acetylcholine receptor and the cryptic epitopes of SARS-Co-V and SARS-CoV-2 Spike glycoproteins. Food Chem Toxicol an Int J Publ Br Ind Biol Res Assoc 149:112009. https://doi.org/10.1016/j.fct.2021.112009

    Article  CAS  Google Scholar 

  58. Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA et al (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89(2):337–343. https://doi.org/10.1046/j.1471-4159.2004.02347.x

    Article  CAS  PubMed  Google Scholar 

  59. Hawkins BT et al (2005) Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors. Am J Physiol Heart Circ Physiol 289(1):H212–H219. https://doi.org/10.1152/ajpheart.01210.2004

    Article  CAS  PubMed  Google Scholar 

  60. Nam HS, Park JW, Ki M, Yeon MY, Kim J, Kim SW (2017) High fatality rates and associated factors in two hospital outbreaks of MERS in Daejeon, the Republic of Korea. Int J Infect Dis IJID Off Publ Int Soc Infect Dis 58:37–42. https://doi.org/10.1016/j.ijid.2017.02.008

    Article  Google Scholar 

  61. Leite FRM, Nascimento GG, Scheutz F, López R (2018) Effect of smoking on periodontitis: a systematic review and metaregression. Am J Prev Med 54:831–841. https://doi.org/10.1016/j.amepre.2018.02.014

    Article  PubMed  Google Scholar 

  62. Han L, Ran J, Mak YW, Suen LK, Lee PH, JSM P, Yang L (2019) Smoking and influenza-associated morbidity and mortality: a systematic review and meta-analysis. Epidemiology (Cambridge, Mass.) 30(3):405–417. https://doi.org/10.1097/EDE.0000000000000984

    Article  PubMed  Google Scholar 

  63. Yu J, Yang P, Qin X, Li C, Lv Y, Wang X (2022) Impact of smoking on the eradication of Helicobacter pylori. Helicobacter 27:e12860. https://doi.org/10.1111/hel.12860

    Article  CAS  PubMed  Google Scholar 

  64. Farsalinos K, Barbouni A, Niaura R (2020d) Smoking, vaping and hospitalization for COVID-19. Qeios. https://doi.org/10.32388/z69o8a.12

  65. Peña S, Ilmarinen K, Kestilä L, Parikka S, Kärkkäinen S, Caspersen IH, Shaaban AN, Magnus P et al (2022) Tobacco use and risk of COVID-19 infection in the Finnish general population. Sci Rep 12:20335. https://doi.org/10.1038/s41598-022-24148-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Caspersen IH, Trogstad L, Galanti MR, Karvonen S, Peña S, Shaaban AN, Håberg SE, Magnus P (2023) Current tobacco use and SARS-CoV-2 infection in two Norwegian population-based cohorts. BMC Public Health 23:846. https://doi.org/10.1186/s12889-023-15822-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Piasecki TM, Smith SS, Baker TB, Slutske WS, Adsit RT, Bolt DM, Conner KL, Bernstein SL et al (2022) Smoking status, nicotine medication, vaccination, and COVID-19 hospital outcomes: findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study. Nicotine Tob Res 25:1184–1193. https://doi.org/10.1093/ntr/ntac201

    Article  PubMed Central  Google Scholar 

  68. Usman MS, Siddiqi TJ, Khan MS, Patel UK, Shahid I, Ahmed J, Kalra A, Michos ED (2021) Is there a smoker's paradox in COVID-19? BMJ Evid-Based Med 26(6):279–284. https://doi.org/10.1136/bmjebm-2020-111492

    Article  PubMed  Google Scholar 

  69. Farsalinos K, Bagos PG, Giannouchos T, Niaura R, Barbouni A, Poulas K (2021) Smoking prevalence among hospitalized COVID-19 patients and its association with disease severity and mortality: an expanded re-analysis of a recent publication. Harm Reduct J 18(9). https://doi.org/10.1186/s12954-020-00437-5

  70. Borroni V, Barrantes FJ (2021) Homomeric and heteromeric α7 nicotinic acetylcholine receptors in health and some central nervous system diseases. Membranes (Basel) 11. https://doi.org/10.3390/membranes11090664

  71. Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73–120. https://doi.org/10.1152/physrev.00015.2008

    Article  CAS  PubMed  Google Scholar 

  72. Fujii YX, Fujigaya H, Moriwaki Y, Misawa H, Kasahara T, Grando SA, Kawashima K (2007) Enhanced serum antigen-specific IgG1 and proinflammatory cytokine production in nicotinic acetylcholine receptor α7 subunit gene knockout mice. J Neuroimmunol 189:69–74. https://doi.org/10.1016/j.jneuroim.2007.07.003

    Article  CAS  PubMed  Google Scholar 

  73. Shinu P, Morsy MA, Deb PK, Nair AB, Goyal M, Shah J, Kotta S (2020) SARS CoV-2 organotropism associated pathogenic relationship of gut-brain axis and illness. Front Mol Biosci 7:1–8. https://doi.org/10.3389/fmolb.2020.606779

    Article  CAS  Google Scholar 

  74. Blanchet M-R, Israël-Assayag E, Daleau P, Beaulieu M-J, Cormier Y (2006) Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation. Am J Physiol Lung Cell Mol Physiol 291(4):L757–L763. https://doi.org/10.1152/ajplung.00409.2005

    Article  CAS  PubMed  Google Scholar 

  75. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Förster I, Akira S (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of stat3 in macrophages and neutrophils. Immunity 10:39–49. https://doi.org/10.1016/S1074-7613(00)80005-9

    Article  CAS  PubMed  Google Scholar 

  76. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S et al (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6:844–851. https://doi.org/10.1038/ni1229

    Article  CAS  PubMed  Google Scholar 

  77. Maldifassi MC, Atienza G, Arnalich F, López-Collazo E, Cedillo JL, Martín-Sánchez C, Bordas A, Renart J et al (2014) A new IRAK-M-mediated mechanism implicated in the anti-inflammatory effect of nicotine via α7 nicotinic receptors in human macrophages. PloS One 9,9:e108397. https://doi.org/10.1371/journal.pone.0108397

    Article  CAS  PubMed  Google Scholar 

  78. Zhang B, Yu J-Y, Liu L-Q, Peng L, Chi F, Wu C-H, Jong A, Wang S-F et al (2015) Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury related CNS disorders caused by Cryptococcus neoformans and HIV-1 associated comorbidity factors. BMC Infect Dis 15:352. https://doi.org/10.1186/s12879-015-1075-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dosch SF, Mahajan SD, Collins AR (2009) SARS coronavirus spike protein-induced innate immune response occurs via activation of the NFkappaB pathway in human monocyte macrophages in vitro. Virus Res 142(1-2):19–27. https://doi.org/10.1016/j.virusres.2009.01.005

    Article  CAS  PubMed  Google Scholar 

  80. Dormoy V, Perotin JM, Gosset P, Maskos U, Polette M, Deslée G (2022) Nicotinic receptors as SARS-CoV-2 spike co-receptors? Med Hypotheses 158:110741. https://doi.org/10.1016/j.mehy.2021.110741

    Article  CAS  PubMed  Google Scholar 

  81. Russo P, Bonassi S, Giacconi R, Malavolta M, Tomino C, Maggi F (2020) COVID-19 and smoking: is nicotine the hidden link? Eur Respir J 55(6):2001116. https://doi.org/10.1183/13993003.01116-2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Verdecchia P, Cavallini C, Spanevello A, Angeli F (2020) The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med 76:14–20. https://doi.org/10.1016/j.ejim.2020.04.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Letsinger AC, Ward JM, Fannin RD, Mahapatra D, Bridge MF, Sills RC, Gerrish KE, Yakel JL (2023) Nicotine exposure decreases likelihood of SARS-CoV-2 RNA expression and neuropathology in the hACE2 mouse brain but not moribundity. Sci Rep 13:2042. https://doi.org/10.1038/s41598-023-29118-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Li L, Acioglu C, Heary RF, Elkabes S (2021) Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behav Immun 91:740–755. https://doi.org/10.1016/j.bbi.2020.10.007

    Article  CAS  PubMed  Google Scholar 

  85. da Silva Chagas L, Sandre PC, de Velasco PC, Marcondes H, Ribeiro NCA RE, Barreto AL, Alves Mauro LB, Ferreira JH et al (2021) Neuroinflammation and brain development: possible risk factors in COVID-19-infected children. NeuroImmunoModulation 28:22–28. https://doi.org/10.1159/000512815

    Article  CAS  PubMed  Google Scholar 

  86. Choudhury A, Mukherjee S (2020) In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J Med Virol 92:2105–2113. https://doi.org/10.1002/jmv.25987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651. https://doi.org/10.1101/cshperspect.a001651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kobayashi K, Hernandez LD, Galán JE, Janeway CA Jr, Medzhitov R, Flavell RA (2002b) IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110:191–202. https://doi.org/10.1016/s0092-8674(02)00827-9

    Article  CAS  PubMed  Google Scholar 

  89. Hubbard LLN, Moore BB (2010) IRAK-M regulation and function in host defense and immune homeostasis. 2:22–29. https://doi.org/10.4081/idr.2010.e9

    Article  Google Scholar 

  90. Fukao T, Koyasu S (2003) PI3K and negative regulation of TLR signaling. Trends Immunol 24:358–363. https://doi.org/10.1016/S1471-4906(03)00139-X

    Article  CAS  PubMed  Google Scholar 

  91. Fan H, Cook JA (2004) Molecular mechanism of endotoxin tolerance. J Endotoxin Res 10:71–84. https://doi.org/10.1179/096805104225003997

    Article  CAS  PubMed  Google Scholar 

  92. Biswas SK, Lopez-Collazo E (2009) Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol 30(10):475–487. https://doi.org/10.1016/j.it.2009.07.009

    Article  CAS  PubMed  Google Scholar 

  93. Zacharioudaki V, Androulidaki A, Arranz A, Vrentzos G, Margioris AN, Tsatsanis C (2009) Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expression. J Immunol (Baltimore, Md. : 1950) 182(10):6444–6451. https://doi.org/10.4049/jimmunol.0803694

    Article  CAS  Google Scholar 

  94. Ioanna Pantazi, Ahmed A. Al-Qahtani, Fatimah S Alhamlan, Hani Alothaid, Sabine Matou-Nasri, George Sourvinos, Eleni Vergadi, Christos Tsatsanis“SARS-CoV-2/ace2 interaction suppresses IRAK-M expression and promotes pro-inflammatory cytokine production in macrophages.” Front Immunol vol. 12 683800. 23 Jun. 2021, https://doi.org/10.3389/fimmu.2021.683800

  95. Lyroni K, Patsalos A, Daskalaki MG, Doxaki C, Soennichsen B, Helms M, Liapis I, Zacharioudaki V et al (2017) Epigenetic and transcriptional regulation of IRAK-M expression in macrophages. J Immunol (Baltimore, Md. : 1950) 198(3):1297–1307. https://doi.org/10.4049/jimmunol.1600009

    Article  CAS  Google Scholar 

  96. Matsuyama S, Nao N, Shirato K, Kawase M, Saito S, Takayama I, Nagata N, Sekizuka T et al (2020) Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci U S A 117(13):7001–7003. https://doi.org/10.1073/pnas.2002589117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G et al (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181:271–280.e8. https://doi.org/10.1016/j.cell.2020.02.052

    Article  PubMed  PubMed Central  Google Scholar 

  98. Sohn KM, Lee SG, Kim HJ, Cheon S, Jeong H, Lee J, Kim IS, Silwal P et al (2020) COVID-19 patients upregulate toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis. J Korean Med Sci 35:e343. https://doi.org/10.3346/jkms.2020.35.e343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Nirthanan S (2020) Snake three-finger α-neurotoxins and nicotinic acetylcholine receptors: molecules, mechanisms and medicine. Biochem Pharmacol 181:114168. https://doi.org/10.1016/j.bcp.2020.114168

    Article  CAS  PubMed  Google Scholar 

  100. Akaike Ak, Izumi Y (2018)Overview. In: Akaike A et al(eds) Nicotinic acetylcholine receptor signaling in neuroprotection, Springer, pp 1–15. https://doi.org/10.1007/978-981-10-8488-1_1

  101. Nakayama K, Okugawa S, Yanagimoto S, Kitazawa T, Tsukada K, Kawada M, Kimura S, Hirai K et al (2004) Involvement of IRAK-M in peptidoglycan-induced tolerance in macrophages *. J Biol Chem 279:6629–6634. https://doi.org/10.1074/jbc.M308620200

    Article  CAS  PubMed  Google Scholar 

  102. Escoll P, del Fresno C, García L, Vallés G, Lendínez MJ, Arnalich F, López-Collazo E (2003) Rapid up-regulation of IRAK-M expression following a second endotoxin challenge in human monocytes and in monocytes isolated from septic patients. Biochem Biophys Res Commun 311(2):465–472. https://doi.org/10.1016/j.bbrc.2003.10.019

    Article  CAS  PubMed  Google Scholar 

  103. Olds JL, Kabbani N (2020) Is nicotine exposure linked to cardiopulmonary vulnerability to COVID-19 in the general population? FEBS J 287(17):3651–3655. https://doi.org/10.1111/febs.15303

    Article  PubMed  PubMed Central  Google Scholar 

  104. Gonzalez-Rubio J, Navarro-Lopez C, Lopez-Najera E, Lopez-Najera A, Jimenez-Diaz L, Navarro-Lopez JD, Najera A (2020) Cytokine Release Syndrome (CRS) and nicotine in COVID-19 patients: trying to calm the storm. Front Immunol 11:1359. https://doi.org/10.3389/fimmu.2020.01359

  105. Reitsma MB, Fullman N, Ng M, Salama JS, Abajobir A, Abate KH, Abbafati C, Abera SF et al (2017) Smoking prevalence and attributable disease burden in 195 countries and territories, 1990–2015: a systematic analysis from the Global Burden of Disease Study 2015. Lancet 389:1885–1906. https://doi.org/10.1016/S0140-6736(17)30819-X

    Article  Google Scholar 

  106. Arcavi L, Benowitz NL (2004) Cigarette smoking and infection. Arch Intern Med 164:2206–2216. https://doi.org/10.1001/archinte.164.20.2206

    Article  PubMed  Google Scholar 

  107. Blagev DP, Harris D, Dunn AC, Guidry DW, Grissom CK, Lanspa MJ (2019) Clinical presentation, treatment, and short-term outcomes of lung injury associated with e-cigarettes or vaping: a prospective observational cohort study. Lancet 394:2073–2083. https://doi.org/10.1016/S0140-6736(19)32679-0

    Article  PubMed  Google Scholar 

  108. Madison MC, Landers CT, Gu BH, Chang CY, Tung HY, You R, Hong MJ, Baghaei N et al (2019) Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine. J Clin Invest 129:4290–4304. https://doi.org/10.1172/JCI128531

    Article  PubMed  PubMed Central  Google Scholar 

  109. Ahmad F (2020) COVID-19 induced ARDS, and the use of galantamine to activate the cholinergic anti-inflammatory pathway. Med Hypotheses 145:110331. https://doi.org/10.1016/j.mehy.2020.110331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Malek N, Greene J (2014) Scott Med J. https://doi.org/10.1177/0036933014561948

  111. Malek N, Greene J (2015) Cognition enhancers for the treatment of dementia. Scott Med J 60:44–49. https://doi.org/10.1177/0036933014561948

    Article  PubMed  Google Scholar 

  112. Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G (2017) Neuroinflammation pathways: a general review. Int J Neurosci 127(7):624–633. https://doi.org/10.1080/00207454.2016.1212854

    Article  CAS  PubMed  Google Scholar 

  113. Liu B, Gu Y, Pei S, Peng Y, Chen J, Pham LV, Shen HY, Zhang J et al (2019) Interleukin-1 receptor associated kinase (IRAK)-M -mediated type 2 microglia polarization ameliorates the severity of experimental autoimmune encephalomyelitis (EAE). J Autoimmun 102:77–88. https://doi.org/10.1016/j.jaut.2019.04.020

    Article  CAS  PubMed  Google Scholar 

  114. Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53. https://doi.org/10.1038/nrn1824

    Article  CAS  PubMed  Google Scholar 

  115. Figley CR, Stroman PW (2011) The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals. Eur J Neurosci 33:577–588. https://doi.org/10.1111/j.1460-9568.2010.07584.x

    Article  PubMed  Google Scholar 

  116. Piet R, Vargová L, Syková E, Poulain DA, Oliet SH, Wang H (2004) Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc Natl Acad Sci U S A 101:2151–2155. https://doi.org/10.1073/pnas.0308408100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Revathikumar P, Bergqvist F, Gopalakrishnan S, Korotkova M, Jakobsson P-J, Lampa J, Le Maître E (2016) Immunomodulatory effects of nicotine on interleukin 1β activated human astrocytes and the role of cyclooxygenase 2 in the underlying mechanism. J Neuroinflammation 13:256. https://doi.org/10.1186/s12974-016-0725-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, O'Dea MR, Dutton S et al (2022) Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 185:2452–2468.e16. https://doi.org/10.1016/j.cell.2022.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Itay L, Nishiyama S, Manzano GS, Lydston M, Levy M (2022) COVID-19 and the risk of CNS demyelinating diseases: A systematic review. Front Neurol 13:970383. https://doi.org/10.3389/fneur.2022.970383

  120. Aryal SP, Fu X, Sandin JN, Neupane KR, Lakes JE, Grady ME, Richards CI (2021) Nicotine induces morphological and functional changes in astrocytes via nicotinic receptor activity. Glia 69:2037–2053. https://doi.org/10.1002/glia.24011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Forrester JV, McMenamin PG, Dando SJ (2018) CNS infection and immune privilege. Nat Rev Neuroscience 19(11:655-671. https://doi.org/10.1038/s41583-018-0070-8

  122. Zane J, Ula M, Anna G, Vivek S, Barrett Nicholas A, Lucy C, Manu S-H, Maria T et al (2020) Microvascular injury and hypoxic damage : emerging neuropathological signatures in COVID - 19. Acta Neuropathol 140:397–400. https://doi.org/10.1007/s00401-020-02190-2

    Article  CAS  Google Scholar 

  123. Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, Mushumba H, Fitzek A et al (2020) Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol 19(11):919–929. https://doi.org/10.1016/S1474-4422(20)30308-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Najjar S, Najjar A, Chong DJ, Pramanik BK, Kirsch C, Kuzniecky RI, Pacia SV, Azhar S (2020) Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation 17:1–14. https://doi.org/10.1186/s12974-020-01896-0

    Article  CAS  Google Scholar 

  125. Baig AM, Khaleeq A, Ali U, Syeda H (2020b) Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 11(7):995–998. https://doi.org/10.1021/acschemneuro.0c00122

    Article  CAS  PubMed  Google Scholar 

  126. Qi J, Zhou Y, Hua J, Zhang L, Bian J, Liu B, Zhao Z, Jin S (2021a) The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to SARS-CoV-2 infection. Int J Environ Res Public Health 18(1):284. https://doi.org/10.3390/ijerph18010284

  127. Qi J, Zhou Y, Hua J, Zhang L, Bian J, Liu B, Zhao Z, Jin S (2021b) The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to SARS-CoV-2 infection. Int J Environ Res Public Health 18(1):284. https://doi.org/10.3390/ijerph18010284

  128. Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J et al (2021) The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Nat Neurosci 24(3):368–378. https://doi.org/10.1038/s41593-020-00771-8

    Article  CAS  PubMed  Google Scholar 

  129. Sharma G, Vijayaraghavan S (2001) Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores. Proc Natl Acad Sci U S A 98:4148–4153. https://doi.org/10.1073/pnas.071540198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (London, England : 1979) 121(9):367–387. https://doi.org/10.1042/CS20110164

    Article  CAS  Google Scholar 

  131. Thakur KT, Miller EH, Glendinning MD, Al-Dalahmah O, Banu MA, Boehme AK, Boubour AL, Bruce SS et al (2021) COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain J Neurol 144(9):2696–2708. https://doi.org/10.1093/brain/awab148

    Article  Google Scholar 

  132. Sinkus ML, Graw S, Freedman R, Ross RG, Lester HA, Leonard S (2016) The human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation, and function. Neuropharmacology. HHS Public Access 96:274–288. https://doi.org/10.1016/j.neuropharm.2015.02.006

    Article  CAS  Google Scholar 

  133. Greene CM, Ramsay H, Wells RJ, O'Neill SJ, McElvaney NG (2010) Inhibition of Toll-like receptor 2-mediated interleukin-8 production in Cystic Fibrosis airway epithelial cells via the alpha7-nicotinic acetylcholine receptor. Mediators Inflamm 2010:423241. https://doi.org/10.1155/2010/423241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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This work was supported by Edital Universal (Conselho Nacional de Desenvolvimento Científico Tecnológico/CNPq—Proc. 405128/2021–5).

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  1. Laboratory of Neuroprotection and Neurometabolic Diseases (Wyse’s Lab), Department of Biochemistry, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre RS, 90035-003, Brazil

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ASR was responsible for data curation, formal analysis, investigation, methodology, roles/writing—original draft, writing—review and editing, design and creation of figures; ATSW was responsible for conceptualization, funding acquisition, project administration, resources, supervision, writing—review and editing.

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Rieder, A.S., Wyse, A.T.S. Regulation of Inflammation by IRAK-M Pathway Can Be Associated with nAchRalpha7 Activation and COVID-19. Mol Neurobiol 61, 581–592 (2024). https://doi.org/10.1007/s12035-023-03567-6

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