Therapeutic targeting of inflammation in hypertension: from novel mechanisms to translational perspective

Abstract

Both animal models and human observational and genetic studies have shown that immune and inflammatory mechanisms play a key role in hypertension and its complications. We review the effects of immunomodulatory interventions on blood pressure, target organ damage, and cardiovascular risk in humans. In experimental and small clinical studies, both non-specific immunomodulatory approaches, such as mycophenolate mofetil and methotrexate, and medications targeting T and B lymphocytes, such as tacrolimus, cyclosporine, everolimus, and rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin scavengers to prevent neo-antigen formation, co-stimulation blockade (abatacept, belatacept), and anti-cytokine therapies (e.g. secukinumab, tocilizumab, canakinumab, TNF-α inhibitors). In many studies, trial designs have been complicated by a lack of blood pressure-related endpoints, inclusion of largely normotensive study populations, polypharmacy, and established comorbidities. Among a wide range of interventions reviewed, TNF-α inhibitors have provided the most robust evidence of blood pressure lowering. Treatment of periodontitis also appears to deliver non-pharmacological anti-hypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are also discussed. The reviewed animal models, observational studies, and trial data in humans, support the therapeutic potential of immune-targeted therapies in blood pressure lowering and in hypertension-mediated organ damage. Targeted studies are now needed to address their effects on blood pressure in hypertensive individuals.

Keywords: Blood pressure; Hypertension; Immune system; Immunomodulatory; Inflammation.

Graphical abstract

Figure 1

Role of the immune system in the pathogenesis of experimental hypertension and potential immunomodulators for the treatment of hypertension and cardiovascular organ damage. Animal studies implicate virtually all immune cell subsets (dash lines) and cytokines (solid lines) in the pathogenesis of hypertension and target organ damage. Initially, classical immunosuppressants such as mycophenolate^, or rapamycin showed improvement in renal damage and blood pressure regulation, by non-specific mechanisms. The introduction of cell/cytokine-specific immunomodulators (small-molecule inhibitors, antibodies, antagonists or scavengers) with beneficial effect in hypertension and hypertension-mediated organ damage, emphasize the potential use of immunomodulators as a pharmacological tool. More details about the inhibitors are presented in Table1. Numbers indicate references represent a positive (green) or negative (red) effect. Legend: CD, cluster of differentiation; CCR, chemokine receptor; Treg, T-regulatory cell; TH, T-helper cell; IL, interleukin; TNF-α, tumour necrosis factor alfa; NF-κB, Nuclear factor kappa B; IFN-γ, interferon γ; NLPR3, NOD-like receptor family, pyrin domain-containing protein 3; TGF-β, transforming growth factor beta; TLR, Toll-like receptor; PEG-sTNFR1, PEGylated soluble tumour necrosis factor receptor 1; TAK-242, inhibitor of TLR4 signalling; 2-HOBA, 2-hydroxybenzylamine; MCC950, small-molecule inhibitor of the NLRP3 pathway; INCB3344, CCR2 antagonist; Met-RANTES, CCR5 antagonist.

Figure 2

Meta-analysis and Forest Plot using random effect model, of TNF-α inhibitor studies reporting SBP outcomes, with reference to average baseline SBP, population size, and study weighting. Effect size reports average change in SBP in mmHg; * indicates ambulatory BP monitoring and MAP indicates only mean arterial pressure data available. Panel A includes cohort studies reporting average SBP prior and subsequent to drug initiation; panel B includes randomized trials with comparison to placebo or other pharmacotherapy. Overall change in average SBP accompanied by 95% confidence interval. ADL, adalimumab; ETN, etanercept; GOL, golimumab; IFX, infliximab; Mixed, different TNF-α inhibitors within the study; SBP, systolic blood pressure; sDMARD, conventional synthetic disease modifying anti-rheumatic; TNF-α, tumour necrosis factor alpha.

Figure 3

Bubble plot illustrating immunomodulatory agents plotted by baseline SBP (x-axis) and average change in SBP (y-axis), both in mmHg, with bubble area representing cohort size. R² = 31% fpr average change in SBP by average baseline SBP. CNI, calcineurin inhibitor; CTLA4-Ig, cytotoxic T-lymphocyte-associated protein 4 immunoglobulin; HCQ, hydroxychloroquine; IL, interleukin; MMF, mycophenolate mofetil; mTOR: mammalian target of rapamycin; MTX: methotrexate; SBP, systolic blood pressure; TNF, tumour necrosis factor.

Figure 4

Renal and immune system effects of calcineurin inhibitors influencing blood pressure. COX2, cyclooxygenase-2; GFR, glomerulofiltration rate; IL-2, interleukin-2; NFAT, nuclear factor of activated T cells; NO, nitric oxide; TMA, thrombotic microangiopathy; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; SNS, sympathetic nervous system; TGF-β, transforming growth factor beta. Created in BioRender.

Figure 5

Immunomodulatory drugs and the level of animal and clinical evidence available regarding blood pressure and organ system outcomes. Summarized according to the aggregated weight of the available evidence. BP, blood pressure; CD, cluster of differentiation; CNI, calcineurin inhibitor; CTLA4-Ig, cytotoxic T-lymphocyte-associated protein 4 immunoglobulin; HCQ, hydroxychloroquine; IL, interleukin; MMF, mycophenolate mofetil; mTOR: mammalian target of rapamycin; MTX: methotrexate; TNF, tumour necrosis factor. *Cardiovascular outcomes. ^Includes arterial stiffness, endothelial function, and cerebrovascular outcomes. ^#Includes chronic kidney disease, end-stage kidney disease, fibrosis, and inflammation.