Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression

Abstract

Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6Chigh monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe−/− mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6Chigh monocytes and macrophages. SYK inhibition limited Ly6Chigh monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe−/− mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-016-0535-8) contains supplementary material, which is available to authorized users.

Monocyte Recruitment Versus Macrophage Proliferation in Atherosclerosis

“…Robbins and coworkers demonstrated in a hallmark paper in 2013 that local proliferation dominates macrophage accumulation in more advanced atherosclerotic lesions 2 . A similar finding was reported by Lindau et al, who demonstrated that reduced circulating monocyte levels only affected early lesions but not more advanced atherosclerotic lesions 11 . In the present study, Li et al demonstrated that myeloid cell deficiency in PKCδ indeed increase macrophage proliferation in the atherosclerotic lesion (figure) 4 .…”

Breast cancers from black women exhibit higher numbers of immunosuppressive macrophages with proliferative activity and of crown-like structures associated with lower survival compared to non-black Latinas and Caucasians

“…These new data demonstrate the embryonal origin of the majority of tissue resident macrophages with self-renewal capabilities, in contrast to macrophages recruited to the tissues after a pathogenic or damaging insult, which in the majority of the cases seem to differentiate from blood monocytes and lack proliferative capacity [48]. Proliferation of macrophages has now been identified in various settings, such as in nematode-infected tissues, obese adipose tissues, glomerulonephritis, atherosclerosis, AIDS-related dementia, and in a variety of murine tumors, when the resident versus inflammatory origin (ontogeny) of these macrophages is in many cases uncertain [49, 50]. Proliferating macrophages have also been recently recognized in human lymphomas and in breast tumors [51–54].…”

Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation

“…In agreement, the SYK inhibitor fostamatinib, administered at the beginning and during feeding Ldlr −/− or Apoe −/− mice a high-cholesterol diet (HCD), reduced monocytosis, vascular inflammation and atherosclerotic lesion size [25, 26]. However, fostamatinib, administered to Apoe −/− mice 8 weeks after the start of HCD feeding, failed to prevent progression of established plaques [26]. In part, this could be explained by degradation of early oxidation products like BEP-CE and diminished role of the TLR4/SYK pathway in advanced atherosclerotic plaques.…”

“…However, under conditions of increased and chronic production of OxCE and OxPE, such as in hyperlipidemia, low-grade but prolonged response would result in chronic inflammation and promote atherosclerosis. In agreement, the SYK inhibitor fostamatinib, administered at the beginning and during feeding Ldlr −/− or Apoe −/− mice a high-cholesterol diet (HCD), reduced monocytosis, vascular inflammation and atherosclerotic lesion size [25, 26]. However, fostamatinib, administered to Apoe −/− mice 8 weeks after the start of HCD feeding, failed to prevent progression of established plaques [26].…”