Interleukin‐6 neutralization ameliorates symptoms in prematurely aged mice

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin‐6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin‐6 activity by tocilizumab, a neutralizing antibody raised against interleukin‐6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G/G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging‐related disorders.

Impact of Progerin Expression on Adipogenesis in Hutchinson—Gilford Progeria Skin-Derived Precursor Cells

“…Reducing chronic inflammation using sodium salicylate, an inhibitor of NF-κB signaling, increased the longevity and increased the body weight of both Lmna G609G/G609G and Zmpste24 −/− mouse models [ 68 ]. Reducing inflammation with tocilizumab, an anti-IL-6 receptor antibody, rescued the differentiation of pre-adipocytes in progeroid mice by increasing the percentage of adipogenic differentiation and the size of lipid droplets [ 69 ]. This treatment improved the terminal differentiation of adipocytes by increasing the fusion of lipid droplets [ 69 ].…”

“…Reducing inflammation with tocilizumab, an anti-IL-6 receptor antibody, rescued the differentiation of pre-adipocytes in progeroid mice by increasing the percentage of adipogenic differentiation and the size of lipid droplets [ 69 ]. This treatment improved the terminal differentiation of adipocytes by increasing the fusion of lipid droplets [ 69 ].…”

Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

“…Reduced the overall hip or knee arthroplasty rate in patients with a history of OA at baseline Schieker et al (2020). Tocilizumab IL-6 receptor Reduced age-related inflammatory responses in premature aging mice Squarzoni et al (2021). Attenuated central sensitization and pain in OA rats Lin et al (2017).…”

“…IL-6 increases the production of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 in chondrocytes, causing degradation of cartilage matrix proteins. Blocking IL-6 causes inhibition of cellular senescence, and alleviates the aging-related inflammation in premature senescent mice ( Squarzoni et al, 2021 ). In addition, tocilizumab ameliorates allyodynia of rat OA ( Lin et al, 2017 ).…”

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

“…Additional genetic and pharmacological strategies have proved successful in reducing or preventing VSMC loss in HGPS-like mice. These strategies include deletion of the matrix metalloprotease 13 ( Mmp13 ) gene, the use of the matrix metalloprotease inhibitor batimastat [ 94 ], and the blockade of interleukin-6 signaling with the neutralizing antibody tocilizumab [ 95 ] in Lmna G609G/G609G mice, suggesting that HGPS-associated VSMC depletion involves ECM remodeling and inflammation. VSMC loss in Lmna G609G/G609G mice was also prevented by inhibition of N-acetyltransferase 10 with remodelin, and this treatment also ameliorated aortic adventitial thickening and extended lifespan [ 96 ].…”