Macrophage release of transforming growth factor β1 during resolution of monosodium urate monohydrate crystal–induced inflammation

Abstract

Objective. It has previously been shown that as monocytes differentiate into macrophages, they lose the ability to secrete proinflammatory cytokines in response to monosodium urate monohydrate (MSU) crystals. The purpose of this study was to investigate whether MSU crystals induce macrophages to secrete antiinflammatory factor instead.Methods. Human monocyte or macrophage isolates were prepared from samples obtained from healthy volunteer donors either by differentiation of blood monocytes in vitro or by collecting cells from skin blisters during the early or late phase of the dermal inflammatory response to cantharidin. Monocyte or macrophage isolates were then incubated with MSU crystals for 24 hours, and culture supernatants were assayed for candidate antiinflammatory mediators (by enzyme-linked immunosorbent assay) and for the capacity to activate or suppress endothelial cell E-selectin expression and secondary neutrophil recruitment under shear flow.Results. Analysis of supernatants from in vitrodifferentiated macrophages revealed that transforming growth factor ␤1 ( The mechanisms behind the spontaneous resolution of gout remain incompletely explained. In the absence of clinical intervention, acute gouty arthritis usually resolves within a few days. However, monosodium urate monohydrate (MSU) crystals can persist in joints following acute inflammation and have been identified within mononuclear cells in synovial fluid aspirated from clinically quiescent knee and metatarsophalangeal joints (1-3). A possible beneficial role of macrophages in gout has been demonstrated with the observation that mouse macrophage cell lines and human in vitro-differentiated macrophages ingest MSU crystals without proinflammatory cytokine secretion or endothelial cell activation (4,5). Such quiescent behavior is in marked contrast to less well-differentiated monocytic isolates, which secrete tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), IL-6, and IL-8, activate E-selectin expression, and promote secondary neutrophil capture by endothelial cells under physiologic flow in response to MSU crystal uptake (5-9).

Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation

“…Importantly, fully differentiated macrophages that clear MSU crystals express TGF␤1, thereby promoting resolution of acute MSU crystal-induced inflammation (4,15). Therefore, our results suggest that under some conditions, TLR-2 and TLR-4 expression might not only promote the triggering of acute gout, but also contribute to the spontaneous self-limitation so characteristic of gouty inflammation (1,4).…”

“…We limited our analysis of cultured cells to unfractionated bone marrow macrophage preparations. The state of differentiation of macrophages clearly mediates the ability of these cells to not only take up MSU crystals (14), but to also respond in a proinflammatory or antiinflammatory manner to the crystals (14,15). Hence, the observed effects of host TLR-2 and TLR-4 expression on the capacity of macrophages to ingest and react to MSU crystals were possibly at least partially mediated by indirect effects on macrophage differentiation.…”

“…The inert MSU crystal has the capacity to avidly bind at least 20 different plasma proteins (1,14,15). Although such MSU crystal binding interactions are nonspecific via hydrogen and electrostatic bonds, MSU does associate preferentially with selected proteins in complex mixtures, as illustrated by apoB and complement pathway protein binding in crystals exposed to human plasma (41,42).…”

“…Release of the neutrophilexpressed calgranulin heterodimer S100A8/A9, one of the most abundant protein constituents of the neutrophil cytoplasm (12), appears to substantially amplify neutrophil recruitment in gouty inflammation (13). Importantly, the state of macrophage differentiation is a major factor in the uptake of MSU crystals and sequelae, including the capacity to express transforming growth factor ␤1 (TGF␤1), a native suppressor of experimental gouty inflammation (14)(15)(16).…”

Evil humors take their toll as innate immunity makes gouty joints TREM‐ble

“…Significantly, tophi are now recognized to continually recruit monocytes that differentiate to macrophages, which is consistent with ongoing remodeling (2). Recently, Yagnik and colleagues elegantly elucidated the capacity of the fully differentiated macrophage to exert antiinflammatory effects on the uptake of MSU crystals (3)(4)(5). Many microscopic intrasynovial tophi appear to be walled-off by a ring of fibrinogen and other proteins (6).…”