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Hypertension: An Immune Disorder?

Kevin J. Tracey1,*1Feinstein Institute, Manhasset, NY 11030, USA*Correspondence: kjtracey@nshs.eduhttp://dx.doi.org/10.1016/j.immuni.2014.11.007

T cell depletion can prevent hypertension in experimental animals. What is the nature of T cell activation inhypertension? In this issue of Immunity, Carnevale et al. (2014) implicate PlGF signaling in a reservoir ofsplenic T cells.

Most immunologists do not list ‘‘hyperten-

sion’’ in their keywords. Scientists inter-

ested in immunity usually focus on he-

matopoietic cells, the cellular responses

to infection and products of sterile injury,

and the genetic mechanisms underlying

signal transduction. But there are notable

exceptions. The history of immunological

approaches to blood pressure has pro-

duced extremely impactful results.

One example is monoclonal anti-tumor

necrosis factor (TNF) antibody therapies,

now used by millions of autoimmune and

autoinflammatory disease patients. The

first experiments using monoclonal anti-

TNF antibodies as an experimental thera-

peutic agent were to prevent low blood

pressure (‘‘shock’’) in baboons infected

with lethal quantities of E. coli (Tracey

et al., 1987). Administration ofmonoclonal

anti-TNF prevented the drop in blood

pressure mediated by TNF. This insight

prompted the pharmaceutical manu-

facturing of TNF mAb. The availability of

these clinical reagents was pivotal to sub-

sequent clinical use in rheumatoid arthritis

and inflammatory bowel disease.

In the United States, 67 million adults,

many of them immunologists, have high

blood pressure. Hypertension is a contrib-

uting factor in the deaths of 350,000, with

an attributed nationwide cost basis

exceeding $45 billion, annually. Despite

the enormity of this health problem, the

mechanisms underlying hypertension are

at best incompletely understood. Under-

lying mechanisms for hypertension can

be established in only 10% of cases.

The remainder is classified as ‘‘essential

hypertension,’’ meaning chronically ele-

vated blood pressure from unknown

causes. Incomplete pathogenic knowl-

edge underlies the inadequate efficacy

of many, if not most, current therapies.

It certainly makes a compelling argu-

ment that new research approaches are

needed. Immunology research may open

the door to new mechanisms.

As reviewed in much greater length and

detail elsewhere, there have been dozens

of studies implicating T lymphocytes and

other hematopoietic cells in the patho-

genesis of essential hypertension in hu-

mans, and in experimental models of

chronic hypertension. Dating back to the

1960s, Okuda and Grollman induced hy-

pertension in naive rats by passively

transferring lymphocytes harvested from

donor rats rendered hypertensive fol-

lowing experimentally induced renal in-

farction (Okuda and Grollman, 1967).

More recently, a seminal study fromDavid

Harrison’s group reported that Rag1�/�

mice failed to develop hypertension in

response to chronic exposure to angio-

tensin II, a standard laboratory model of

chronic hypertension in rodents (Guzik

et al., 2007). Passive transfer of T cells,

but not B cells, restored the hypertensive

response to angiotensin II infusion. A ma-

jor question is what factor(s) activates

T cells to mediate hypertension?

In this issue of Immunity, Carnevale et al.

(2014) observed that placental growth fac-

tor (PlGF)-deficient mice are protected

against hypertension during angiotensin II

infusion. PlGF, a member of the angiogen-

esis family of factors related to vascular

endothelial growth factor (VEGF), is ex-

pressed by cells from the immune and

cardiovascular systems, but whether it

contributed to T cell activation in hyperten-

sion was previously unknown. PlGF-defi-

cient animals were also protected against

T cell mediated inflammation and tissue

injury in the heart, kidney, and aorta that

occurs following angiotensin II infusion.

Surprisingly, the spleen is the reservoir of

these pathogenic T cells. Release of these

cells from spleen during angiotensin II

infusion is controlled by adrenergic neural

signals to spleen that converge on PlGF.

Angiotensin II infusion increased the

expression of tyrosine hydroxylase, the

rate-limiting enzyme in the biosynthesis

of norepinephrine by adrenergic neurons,

and norepinephrine levels in spleen. Abla-

tion of the adrenergic splenic nerve by sur-

gical removal of the celiac ganglion pre-

vented recruitment of pathogenic T cells

from the spleen to the aorta and kidney.

Similar protection against hypertension

ovember 20, 2014 ª2014 Elsevier Inc. 673

Spleen

Vagus nerve

Sympatheticchain

Celiacganglion

Timp3

T cell(Splenic reservoir)

PlGFNE

HypertensionTissue damageTo aorta, other vessels,

kidney etc.

Figure 1. Neural Regulation of Hypertension Mediated by Splenic T CellsNeural signals to spleen culminate in norepinephrine release and increased production of PlGF. Thisenhances expression of Timp3 in T cells that are in turn released from the splenic reservoir. They travelto the aorta, other vessels, and kidney, producing hypertension and tissue damage.

Immunity

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and tissue injury was accomplished by

simply removing the spleen. Reimplanted

spleen from WT donors restored the hy-

pertensive response to angiotensin II.

But mice reimplanted with spleen from

PlGF-deficient donors continued to be

protected against the hypertensive effects

of angiotensin II. The molecular mecha-

nism of PlGF-mediated T cell egress

from spleen is by Sirt1-p53 nucleus pro-

teins, because chronic administration of

the selective inhibitor Ex-527 and genetic

silencing of Sirt1 in PlGF-deficient spleno-

cytes restored the hypertensive response

to angiotensin II. These results are highly

significant because they identify previ-

ously unrecognizedmechanisms of hyper-

tension (Figure 1).

Should we be surprised that immune

signaling and cell-trafficking studies

contribute to basic mechanisms of blood

pressure regulation? Yes and no. ‘‘Yes,’’

if your approach to immunology is

restricted to how information is pro-

cessed by hematopoietic cells to produce

a memory of the events that can be

recalled at a later date. ‘‘No,’’ if your

approach to immunology embraces the

evolutionary role of the immune system

as a major sensory organ on the front

line detecting changes in the milieu inter-

ieur. The ultimate purpose of visceral sen-

sory pathways is tomaintain physiological

homeostasis. This physiological role of

the immune system overlaps the sensory

nervous system.

674 Immunity 41, November 20, 2014 ª2014

The body goes to almost absurd

lengths to maintain blood pressure within

a fairly narrow range. Hematopoietic cells

sense all of the factors that influence

blood pressure-exsanguination, salt

loading, and even angiotensin II infu-

sions—and respond by altering their im-

mune functions, metabolism, and gene

expression. Sensory neuronal activity is

also changed by these factors. Viewed

from the evolutionary perspective, the

nervous and immune systems developed

together on the front line of sensory input.

Maintenance of stable blood pressure

occurs by the integrated output of both

systems.

These results also highlight an opportu-

nity for immunologists. Recent advances

have revealed neural circuits that modu-

late lymphocytes. Mapping the genetic,

molecular, and neurophysiological basis

of the inflammatory reflex also converged

on the spleen (Rosas-Ballina et al., 2011;

Rosas-Ballina et al., 2008). In this proto-

typical circuit, action potentials are trans-

mitted in the vagus nerve to the celiac

ganglion, the origin of the splenic nerve

mentioned above (Andersson and Tracey,

2012). Activation of adrenergic splenic

neurons regulate a T cell subset in splenic

white pulp. These T cells are stimulated by

norepinephrine signaling via beta adren-

ergic receptors to release acetylcholine,

a neurotransmitter that signals via alpha7

nicotinic acetylcholine receptors ex-

pressed by red pulp and marginal zone

Elsevier Inc.

macrophages. The net effect of the action

potentials originating in the vagus nerve is

to inhibit spleen macrophage production

of TNF and other cytokines.

The present findings suggest that we

are at the early stages of understanding

the specificity and sensitivity of neural cir-

cuits that culminate in spleen to regulate

lymphocytes. It is possible to regulate

the inflammatory reflex using implanted

nerve stimulators that inhibit TNF. Early

clinical trials indicate that it might be

possible to treat rheumatoid arthritis,

even in patients refractory to other ther-

apy. Might it be possible to develop phar-

macological or nerve-stimulating strate-

gies to target the PlGF pathway as a

treatment for hypertension? Perhaps.

There are a number of other important

opportunities to further purse this mecha-

nism. What is the T cell receptor for PlGF

signaling? How does norepinephrine

modulate P1GF release or activity? What

is the molecular basis for T cell release

from the splenic reservoir? And how do

PlGF-activated T cells mediate damage

in blood vessels and kidney? Will it be

possible to develop PlGF antibodies to

treat hypertension? These and other an-

swers could impact millions of patients.

REFERENCES

Andersson, U., and Tracey, K.J. (2012). J. Exp.Med. 209, 1057–1068.

Carnevale, D., Pallante, F., Fardella, V., Fardella,S., Iacobucci, R., Federici, M., Cifelli, G., De Lucia,M., and Lembo, G. (2014). Immunity 41, this issue,737–752.

Guzik, T.J., Hoch, N.E., Brown, K.A., McCann,L.A., Rahman, A., Dikalov, S., Goronzy, J.,Weyand, C., and Harrison, D.G. (2007). J. Exp.Med. 204, 2449–2460.

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