Chronic inflammation is of great importance in age-related degeneration. In later life, inflammatory signaling becomes constant and unresolved, in contrast to the short-term, rapidly resolved inflammation that occurs in response to infection and injury in youth. This unresolved inflammation is highly disruptive of tissue function and structure. In response to unrelenting inflammatory signaling, cell behaviors change in pathological ways, such as the deposition of calcium into blood vessel walls, or increasing quiescence of stem cells that should be actively supporting tissue.
Researchers are in search of ways to suppress the excessive inflammation of aging, but so far the only compelling approaches involve removing the causes of inflammatory signaling, such as the growing population of senescent cells. Otherwise interfering in any specific inflammatory signal via the usual means, removing proteins, blocking receptors, and so forth, means suppressing both excessive and appropriate inflammation. It is certainly possible that some signaling is largely only involved in the excessive inflammation of aging, but to date it appears that any effective mechanism to be targeted in the reduction of chronic inflammation is likely also needed in the normal defense against pathogens and potentially cancerous cells.
A greater focus on the causes of chronic inflammation is needed. Beyond senescent cells, the age-damaged environment generates DNA debris, for example, that triggers the innate immune system in the same ways as infection and injury. It is unclear as to what the best solution to clearing this debris might be, but success here is likely to produce greater benefits with fewer side-effects than the search for novel portions of the complex mechanisms of inflammatory signaling that can be blocked to suppress inflammation.
Pathological cardiac remodeling, characterized by left ventricular (LV) hypertrophy, cardiac fibrosis, and inflammation, is a determinant of the clinical course of heart failure (HF). Aging and the activation of the rennin-angiotensin system play an important role in pathological cardiac remodeling. Anti-aging treatments, such as caloric restriction and rennin-angiotensin system-inhibitor use, potentially improve HF by reducing cardiac inflammation. Evidence corroborating the potential benefit of inflammation suppression in reducing cardiovascular disease is increasing. For example, canakinumab, a therapeutic human monoclonal antibody targeting IL-1β, has been shown to significantly lower major adverse cardiovascular event rates. However, the effectiveness of anti-inflammatory therapy in HF awaits full elucidation.
Chemokines and chemokine receptors are important components of the cytokines that orchestrate immune-cell migration and maintain homeostasis. Early research has established that C-C motif chemokine ligand 17 (CCL17) plays an important role in T cell development in the thymus, and it binds to C-C chemokine receptor 4 (CCR4). We have demonstrated that chemokine CCL17, an important regulator of atherosclerosis, is positively associated with coronary artery disease, independent of traditional cardiovascular risk factors. Chemokines are currently believed to be involved in all stages of cardiovascular response to injury and are considered a possible therapeutic target. However, the role of CCL17 in pathological cardiac hypertrophy is yet to be investigated.
Given the current lack of age-related molecules for HF treatment, the elucidation of underlying molecular mechanisms and discovery of potential targets through the combination of clinical cohorts and aging-disease models are warranted. Herein, we report CCL17's tendency to display an age-dependent increase in population studies and potential role as a critical participant in age-related and angiotensin II (Ang II)-induced cardiac hypertrophy and HF. Subsequent animal experiments further revealed that Ccl17 knockout significantly repressed aging and angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological cardiac remodeling in mice. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II-induced pathological cardiac hypertrophy and heart failure.