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The authors hypothesised that the accumulation of macrophages at a site of inflammation induces a shift from an initially proinflammatory macrophage phenotype to a phenotype aimed at suppressing the initiated immune response when sufficient numbers of macrophages have been recruited. To investigate this, the authors cultured monocytes with granulocyte-macrophage colony forming units or macrophage colony forming units into proinflammatory type 1 or anti-inflammatory type 2 macrophages, respectively, in different cell densities. It was found that differentiation of type 1 macrophages in increasing cell densities dramatically lowered tumour necrosis factor α, interleukin (IL)1β and IL6 release. In addition, it increased the production of important factors in the resolution of inflammation such as IL10 and the trophic factors vascular endothelial growth factor and transforming growth factor β (TGFβ). Increasing cell density had no effect on type 2 macrophages. As determined by the use of a range of specific blocking antibodies and trans-well systems, the shift towards a more anti-inflammatory type 1 macrophage depended on cell-cell contact via β2-integrins and was due to a soluble factor. TGFβ, interferon β (IFNβ) and IL6 did not have a role in this phenotypical shift. The proinflammatory phenotype of dendritic cells was also restricted by cell-cell contact leading to a high production of IL10, while the production of IL12p70 was potently reduced. Dendritic cells cultured in low density were strong inducers of T cell proliferation and differentiation into IFNγ-producing cells upon TLR7/8 stimulation. This capability was potently suppressed when dendritic cells were cultured in high cellular density. These data show, for the first time, that cell-cell communication via β2-integrins on type 1 macrophages and dendritic cells restricts their proinflammatory program. This mechanism is likely to be crucial in the suppression of full-blown immune responses, thereby preventing chronic inflammation and possibly tolerance breakthrough.
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