High Blood Pressure Is Not Just a Plumbing Problem: How the Immune System Drives Hypertension

When we think about high blood pressure, we usually picture salt, stiff arteries and a heart working too hard. But over the past two decades, researchers have built a strong case that hypertension is also, in part, an immune and inflammatory disease. A 2024 review in the journal Hypertension by David Harrison and David Patrick pulls this research together and asks a practical question: if the immune system helps drive high blood pressure, can we calm it down?

Immune cells join the blood pressure story

According to the review, a wide cast of immune players, including complement proteins, cytokines, and cells of both the innate and adaptive immune systems, contribute not only to raising blood pressure but also to the damage hypertension does to target organs such as the kidneys and blood vessels. The triggers are familiar ones: a high-salt diet, the hormones aldosterone and angiotensin II, and increased activity of the sympathetic nervous system.

One of the most striking lines of evidence comes from animal experiments. Transferring immune cells from hypertensive animals into non-hypertensive recipients can prime or even cause hypertension in the recipients, which suggests that the immune cells are not just bystanders.

From stressed vessels to activated T cells

The authors describe a possible chain of events. Changes in the physical forces inside small blood vessels, such as pulsatility and shear stress, cause the vessel wall to release signaling molecules. These signals push myeloid cells, such as dendritic cells, to become powerful antigen-presenting cells, the “teachers” of the immune system. These cells, in turn, activate T cells, which are then linked to further vessel and organ injury.

Isolevuglandins: when oxidative stress creates new targets

A central theme, and one the authors’ own groups have studied, involves isolevuglandins (IsoLGs). These are reactive lipid by-products formed during oxidative stress that can attach themselves to proteins. According to the review, peptides modified by IsoLGs are very likely to act as neoantigens, meaning the immune system sees them as “foreign” and mounts a response, helping to activate T cells in hypertension. The same type of process is how the immune system recognizes infected or cancerous cells.

In mouse studies, IsoLG-modified peptides were more abundant in the dendritic cells of hypertensive animals than in normotensive ones. Mopping up IsoLGs with a small molecule called 2-hydroxybenzylamine reduced hypertension and organ damage in experimental models, and transferring dendritic cells loaded with IsoLGs primed hypertension in recipient mice.

The review also connects this to autoimmune disease. Lupus is commonly accompanied by hypertension, and in mouse models, IsoLGs were linked to lower levels of complement protein C1q, which has been tied to lupus-associated hypertension.

The nervous system talks to the immune system

The review also looks at neurogenic mechanisms. Nerve signals can modulate immune cells, and one study cited found that activating nicotinic acetylcholine receptors on macrophages from young, pre-hypertensive rats paradoxically increased inflammatory cytokines. This hints that the body’s normal “inflammatory reflex,” which usually dampens inflammation, may already be altered early in hypertension.

What this could mean for treatment

The authors discuss interventions that might quiet this inflammatory process in hypertension and related cardiovascular disease. Two themes stand out. First, timing matters: they emphasize starting either conventional or immune-modulating treatment early, and looking for approaches that can reverse existing organ damage, not just prevent it. Second, because broadly suppressing the immune system carries obvious risks, they find approaches that do not overtly impair immune function especially attractive, for example dietary changes that influence the gut microbiome and immune responses, which they say deserve future study. The review also notes that markers of inflammation such as C-reactive protein (CRP) might help predict who develops hypertension, although sex and race would need to be considered in any such strategy.

Important caveats

This is a review article, not a new clinical trial, and much of the mechanistic evidence comes from animal models. Immune-targeted blood pressure therapies are still largely investigational. If you or someone you know is treated for high blood pressure, existing medications and lifestyle measures remain the standard of care and should not be changed without talking to a doctor.

Sources and related reading

·         Original paper: Harrison DG, Patrick DM. Immune Mechanisms in Hypertension. Hypertension. 2024;81(8):1659-1674. DOI: 10.1161/HYPERTENSIONAHA.124.21355

·         Free author manuscript: Immune mechanisms in hypertension (PubMed Central)

·         Related: Therapeutic targeting of inflammation in hypertension: from novel mechanisms to translational perspective, a review of immunomodulatory drugs tested for blood pressure and organ damage

·         Related: Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension

Source: High Blood Pressure Is Not Just a Plumbing Problem: How the Immune System Drives Hypertension