locus ceruleus ventilation

Coivd-19 patients have difficulty breathing.  Is this due to lost of lung capacity, the cytokine storm, or a combination of the two?  The neurons of the locus ceruleus are themselves very sensitive to CO₂/pH. [1]  The A6 norepinepthrine releasing neurons of the LC play a role in translating changes in CO₂/pH  to changes in respiration. [2]  This post started asking if cytokines in the Covid-19 cytokine storm effect neurons in the locus ceruleus.

From the peritoneum to the brain

Borsody and Weiss(2005) followed up on previous studies that  demonstrated that ip injection of microbial substances–

• lipopolysaccharide, peptidoglycan bacteria
• poly-inosine: poly-cytosine (poly(I):(C))  RNA viruses—

increased the spontaneous discharge rates and sensory-evoked responses of isolated locus coeruleus (LC) neurons in a dose- and time-related manner in rats.  Complete transection of the subdiaphragmatic vagus nerves abolished this response.  A variety of microbial substances excited LC neurons after administration into the peritoneal cavity in a manner involving the subdiaphragmatic vagus nerves.[3]  Perhaps these studies have ramifications of any bacterial or viral sepsis.

IL-1

Both i.p. peptidoglycan and poly(I)/(C) increased LC activity but with lesser efficacy than LPS.   Was this due to the inflammatory cytokine interleukin 1 (IL-1)? IL-1 receptor antagonists ( IL-1RA) reversed the increase in the activity of LC neurons caused by i.p. peptidoglycan treatment; however, that caused by i.p. Poly(I)/(C) was not diminished by IL-1RA. Thus, the increased activity of LC neurons caused by LPS and peptidoglycan requires IL-1 receptor binding, suggesting the involvement of endogenously-produced IL-1. In contrast, poly(I)/(C) increased the activity of LC neurons but this did not critically involve IL-1 receptors in the LC. [4].

IL-2

Receptors for interleukin 2 are  generally considered to be expressed in memory and regulatory T cells. The early 1990s saw  interest in the neuro-immune axis.  De Sarro and Nisticó injected recombinant human and rat IL-2 into the locus ceruleus of rat brains and measured electrical activity.  [5].  IL-2 injection caused slow wave sleep like patterns that were disrupted by agents that inhibit the heterotrimeric G protein signalling that is used by many cytokines receptors as well as cannabinoid receptors  [5]

IL-6 in combination with IL-1

Ventricles of  mice were injected with interleukin IL-1β (0.5 μg) and  IL-6 (1 μg) [6]  IL-1β and IL-6-dependent LC neuronal activation induced depression-like behavior and IL-1β induced increase in leptin levels enhanced α1-adrenoceptor-mediated depression-like behavior.

IL-7 and IL-10

Not addressed directly in the literature, i.e. PubMed searches.

IP-10 aka Cxcl 10

Cxcl-10 in an interferon gamma induced secreted protein that is a well established component of the Covid-19 cytokine storm. [7]  Cxcl 10 has also been speculated to be responsible for loss of taste and smell in Covid-19 infections.

 GM-CSF

Granulocyte-macrophage colony-stimulating factor is being explored as a therapeutic target for Coivd-19 via antibodies against this secreted pro-inflammatory cytokine as well as its receptor [8].  Myeloid cells activated by GM-CSF may secrete inflammatory cytokines IL-1 and IL-6 as well as reactive oxygen species. [8]  IFNγ prevents secretion of GM-CSF and  fatal HSV1 encephalitis  caused  by the invasion of the brain stem by inflammatory monocytes and neutrophils [9].

MCP-1, aka CCL2

(TNF-α), chemokine (C-C-motif) ligand 2 (CCL2), and granulocyte-macrophage colony-stimulating factor (GM-CSF). A recent review lists these cytokines as part of the COVID-19 cytokine storm:  IL-6)\, IL-1β, TNF-α,  GM-CSF, and CCL2. [10]  The Kempurai does a nice job of reviewing the Covid-19 virus and the cytokine storm.  Then the authors discuss locus ceruleus psychological aspects of Covid-19 such as

• tension that can increase shortness of breath
• sleeping disorders
• fear and anxiety

Another story found that patients with mood disorders or suicide attempt were more likely to be sero positive for Coivd-19 and influenza A and B viruses. [11]  The effect of viral associated cytokines on expression of enzymes involved in serotonin synthesis was speculated to be be part of the iteology. [11]

MIP-IA

Macrophage inflammatory protein (MIP-1) may also induce the secretion of IL-1, IL-6, and TNFα .

TNFα,

Keneko and coworkers [12] injected mice with lipopolysaccharide and found that this stimulated microglial cells to produce TNF-α.  They also found that NE from the locus ceruleus suppressed this inflammatory response.  The influence on respiration was not addressed.

H5N1 and ventilation

The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20% ↓) at 2 days post infection (dpi) and death at 7 dpi in mice  The authors cited four centers of the ventilation in repose to hypoxia and/or elevated CO2

1.  Glomus cells in the carotid body.   Viral nucleocapsid protein NP was not found at this site.
2. NE secreting neurons in locus coeruleus (LC).  These neurons are sensitive to local acidosis.  Viral NP was found in 35% of tyrosine hydroxylase posititive neurons.
3. In serotonergic neurons in the raphe nuclei, 10% of the  tryptophan hydrolase  expressing neurons were also positive for viral NP.
4. The neurokinin 1 receptor (NK1R)-expressing neurons in the retrotrapezoid nucleus (RTN) are chemosensitive and responsible for  HCVR. Viral NP was found in 20% of the neurons.

The authors  asked whether the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intra nasally inoculated with saline or the HK483 virus were exposed to hypercapnia for 5 min at 0, 2, 4, or 6 dpi, followed by immunohistochemistry to determine the expression of nucleoprotein of H5N1 influenza A (NP) alone ….[13]

Mice lacking the used mice with a targeted deletion of the Recombinant activating gene 1  (Rag1^{−/− )}   lack functioning T and B cells.  They can mount an innate but not adaptive immune response against the H1N1 virus. A 2016 study out of the Karolinska Institute tested the hypothesis that the H1N1 virus  could lead to narcolepsy like symptoms in immune compromised rats.   These authors discussed the autoimmune like loss of orexin secreting neurons in the lateral hypothalamus and the possible role of the H1N1 vaccine.

When the nasal passages of the mice were inoculated with H1N1, sleep/wake disturbances followed in a few weeks. [14]  These authors observed viral infection of the noradrenergic neurons of the locus ceruleus. [14]

 

References

1. de Carvalho D, Patrone LG, Taxini CL, Biancardi V, Vicente MC, Gargaglioni LH. (2014) Neurochemical and electrical modulation of the locus coeruleus: contribution to CO2drive to breathe. Front Physiol. 2014 Aug 5;5:288. [PMC free article]
2. Magalhães KS, Spiller PF, da Silva MP, Kuntze LB, Paton JFR, Machado BH, Moraes DJA. (2018) Locus Coeruleus as a vigilance centre for active inspiration and expiration in rats. Sci Rep. 2018 Oct 23;8(1):15654. [PubMed free article]
3. Borsody MK, Weiss JM.(2005) The subdiaphragmatic vagus nerves mediate activation of locus coeruleus neurons by peripherally administered microbial substances. Neuroscience. 2005;131(1):235-45
4. Borsody MK , Jay M Weiss JM (2004) The effects of endogenous interleukin-1 bioactivity on locus coeruleus neurons in response to bacterial and viral substances Brain Res 1007(1-2):39-56.
5. De Sarro G, Nisticó G. (1991) Effects of pertussis toxin, dibutyryl-cyclic-AMP, bromo-cyclic-AMP and forskolin on the behavioural and electrocortical power spectrum changes induced by microinfusion of interleukin-2 into the locus coeruleus. Int J Neurosci. 1991 Jul;59(1-3):67-79
6. Kurosawa N, Shimizu K, Seki K(2016) The development of depression-like behavior is consolidated by IL-6-induced activation of locus coeruleus neurons and IL-1β-induced elevated leptin levels in mice. Psychopharmacology (Berl). 2016 May;233(9):1725-37.
7. Oliviero A, de Castro F, Coperchini F, Chiovato L, Rotondi M. (2020) COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator? Neuroscientist. 2020 Jul 13:1073858420939033. [Cross Ref]
8. Lang FM, Lee KM, Teijaro JR, Becher B, Hamilton JA. (2020) GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches. Nat Rev Immunol. 2020 Jun 23:1-8 [PMC free article]
9. Ramakrishna C, Cantin EM. (2018) IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis. PLoS Pathog. 2018 Jan 19;14(1):e1006822. [PMC free article]
10. Kempuraj D, Selvakumar GP, Ahmed ME, Raikwar SP, Thangavel R, Khan A, Zaheer SA, Iyer SS, Burton C, James D, Zaheer A. (2020) COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist. 2020 Jul 18:1073858420941476 [Cross Ref]
11. Okusaga O, Yolken RH, Langenberg P, Lapidus M, Arling TA, Dickerson FB, Scrandis DA, Severance E, Cabassa JA, Balis T, Postolache TT.(2011) Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts. Version 2. J Affect Disord. 2011 Apr;130(1-2):220-5. [PMC free article]
12. Kaneko YS, Mori K, Nakashima A, Sawada M, Nagatsu I, Ota A. (2005)Peripheral injection of lipopolysaccharide enhances expression of inflammatory cytokines in murine locus coeruleus: possible role of increased norepinephrine turnover. J Neurochem. 2005 Jul;94(2):393-404. [PMC free article]
13. Zhuang J, Zang N, Ye C, Xu F.(2019)Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice. Am J Physiol Lung Cell Mol Physiol. 2019 Mar 1;316(3):L525-L536.[PMC free article]
14. Tesoriero C, Codita A, Zhang MD, Cherninsky A, Karlsson H, Grassi-Zucconi G, Bertini G, Harkany T, Ljungberg K, Liljeström P, Hökfelt TG, Bentivoglio M, Kristensson K.(2016) H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice.
    Proc Natl Acad Sci U S A. 113(3):E368-77. [PMC free article]