Systolic Blood Pressure and Innate Immunity vs. the Cancer Brain

Participants with a valid heart disease phenotype (atherosclerosis) were identified in a MESA blood pressure analysis conducted over 10 years. The valid group varied from 770 to 1113 patients from whom further blood analysis queried a primary and exploratory hypothesis of immune cell subsets. Four statistically significant innate cell subsets were discovered to be associated with Systolic blood pressure (SBP); Natural Killer (NK) cells, gamma delta T cells and classical monocytes.

Separately, an analysis of 7017 individuals from 6 international studies of gene expression signatures for SBP, diastolic blood pressure (DBP) and hypertension (HTN) found 7717 genes of which 34 were most differentialy expressed. Enrichment analysis for the systolic and diastolic gene group's associated to NK cell mediated cytotoxicity and 13 other pathways including antigen processing and inflammatory response, pointing strongly to innate and adaptive immunity. MYADM was the only gene identified for all groups SBP, DBP and HTN.

MYADM controls endothelial barrier function through ezrin, radixin, and moesin (ERM)-dependent regulation of ICAM-1 expression. ERM expression is required for ICAM-1 expression in response to MYADM suppression or TNF-α. ICAM-1 is a paradigmatic adhesion receptor that regulates leukocyte adhesion together with integrin LFA-1. This connection between endothelial membrane and cortical actin cytoskeleton appears to modulate the inflammatory response at the blood tissue barrier. 

Pressure overload activates the sympathetic nervous system (SNS) and up-regulates p53 expression in the cardiac endothelium and in bone marrow (BM) cells. Increased p53 expression promotes endothelial-leukocyte cell adhesion and initiates inflammation in cardiac tissue, which exacerbates systolic dysfunction. SNS activates, at least by significant increase of circulating norepinephrine (NE), which up-regulates p53 expressions, while forced expression of p53 increased ICAM-1 expression. 

On endothelial cells SNS is mediated via catecholamine-β2-adrenergic signaling, which up-regulates the production of reactive oxygen species (ROS), activates p53 and induces cellular senescence. Immune cells, including macrophages, monocytes, NK cells, B and T cells express the β2-adrenergic receptor and catecholamine. During pressure overload, NE cultured macrophages up-regulated p53 expression, whereas introduction of p53 increased Itgal (LFA-1) expression (which binds ICAM-1). Treatment with NE increased ROS, which was attenuated after inhibition of β2- adrenergic signaling in macrophages. Endothelial cell–macrophage interaction via NE-ROS-p53 signaling induces up-regulation of adhesion molecules, thus contributing to cardiac inflammation and systolic dysfunction.

During hypertension the vascular endothelium activates monocytes, in part through ROS by a loss of nitric oxide (NO) signaling, increased release of IL-6, hydrogen peroxide and a parallel increase in STAT activation in adjacent monocytes. NO inhibits formation of intermediate monocytes and STAT3 activation. Humans with hypertension have increased intermediate and non-classical monocytes and  intermediate monocytes demonstrate evidence of STAT3 activation. Mice with experimental hypertension exhibit increased aortic and renal infiltration of monocytes, dendritic cells, and macrophages with activated STAT3.

A senescence-associated secretory phenotype (SASP) was induced in epithelial cells after DNA damage of sufficient magnitude. In premalignant epithelial cells SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy by a paracrine mechanism that largely depended interleukin (IL)-6 and IL-8. Strikingly, loss of p53 and gain of oncogenic RAS exacerbated the pro-malignant activities. This suggests a cell-non-autonomous mechanism by which p53 can restrain and oncogenic RAS can promote the development of age-related cancer by altering the tissue microenvironment. Oncogenic signaling pathways inhibit the p53 gene transcription rate through a mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo. Blocking Stat3 in cancer cells up-regulates expression of p53, leading to p53-mediated tumor cell apoptosis. 

Induced stretch or stretch from pressure overload may engage a non-autonomous, p53 centric micro-mechanical mechanism that escalates or deescalates innate responses against cells functioning outside the mechanical ranges that macrophages or NK cells permit. Thus, the neuro-immune extension through SNS signaling, may begin with circulating blood pressure or stretch promoted through inflammation. 

Blood Pressure by Natural Killer Cells and SARS-CoV2

A meta-analysis of gene expression signatures for diastolic, systolic blood pressure and hypertension found that out of 7717 unique, related genes 34 were most differentialy expressed across 7017 individuals from 6 international studies. No less than 20% of the 34 gene's, were located on Chromosome 19. Enrichment analysis for the diastolic and systolic gene group's associated to Natural Killer (NK) Cell mediated cytotoxicity and 13 other pathways including antigen processing and inflammatory response, pointing strongly to innate and adaptive immunity. 

I covered the NK origin of MHC and antigen immunity and reproduction at Chromosome 19 on a previous blog, now the meta-analysis adds infection, immunity and blood pressure to this location. Evolutionary detectives tracked events from Chromosome 19 to 1,6 and 9 via transposon re-combination events, which provided further direction for interpreting the blood pressure meta-analysis. A review of the genes and pathways involved increasingly characterized innate immunity as an integrated core component of almost every aspect of our skeletal, circulatory, tissue and neuronal systems. 

Blood pressure is enormously complex, but its governance of entropy under the mechanical laws of molecular diffusion and disassociation reign supreme. Renin-Angiotensin (RAS) genes are widely recognized to be the cornerstones needed for blood pressure. Innate immune cells including NK have been confirmed to possess and express RAS genes. Macrophages, a member of innate immune system have been linked to angiotensin signaling neuropathic pain as well as bacterial infection inducing pain suppression by angiotensin 2 receptor (AT2R).  Maternal NK cells AT1R and AT2R have been implicated in the control of localized blood pressure in placental tissues leading to preeclampsia a condition in pregnancy.

In various studies, including in disease conditions it has been shown and suggested that different male:female ratios between AT1R and AT2R in monocytes and other innate cells is an important factor in the determination of blood pressure that has been extensively studied in heart and lung conditions. AT2R plays a critical role in satellite cell differentiation and skeletal muscle regeneration via myoblasts, which may be the reason it's expressed ubiquitously in developing fetal tissue. It's likely that balance between AT1R and AT2R signaling is critical for normal muscle regeneration.  

In addition to the role of NK cells in blood pressure a study using lung-intravital microscopy linked pulmonary NK cells to the control of neutrophil intravascular motility, response to acute inflammation and diminished pathogenic accumulation. NK cell derived IFN-γ plays an important role in the activation and maturation of monocytes into macrophages and dendritic cells, an amplifying mechanism in the early innate inflammatory response. Angiotensin II can induce rapid neutrophil infiltration via AT1R that also stimulates leucocyte–endothelium interactions. Inhibited IFN-γ signaling ameliorated Angiotensin II induced cardiac damage, which led to a finding that NK-cells play an essential role in the induced vascular dysfunction.

Ace2 Expression Patterns in Covid19

Pathophysiology of Covid19 demonstrates that NK cells are depleted and neutrophils infiltrate into lung tissue leading to tissue damage and escalation of the disease. By SARS-CoV2 binding the Ace2 receptor of vascular epithelial and other cells, the conversion of Angiotensin II is blocked (image above), therefore upregulated. Increased levels of Angiotensin II were shown to induce NK cells to release IFN-γ. On recruitment to inflammatory sites, NK-cells release IFN-γ and engage with monocytes in a reciprocal program of activation in which monocytes mature into macrophages and dendritic cells. NK exhaustion results and is a known outcome that may relate to IFN-γ levels. However, in patients with high expression of Ace2, NK cell counts are lower and cytokine expressions do not show up during the initial disease state pointing to the role of accumulating Angiotensin II.  

Covid19 Meta Analysis

The image above shows distribution of expression (y axis) for ACE2, PCSKs (blood pressure mediation) and TMPRSS2 (CoV2 S1 cleavage) across lung cell types (x axis). It completes the picture that Corin-Furin mediated control over blood pressure normalization is a significant component of Covid19 disease progression and NK cells are a central player.

Molecules targeting RAS are a major focus of inhibitory or complementary therapeutic design, but a modified NK cell that is shielded from SARS-CoV2 may be the tool-in-the-shed our immune systems need.