Bidirectional crosstalk via IL-6, PGE2 and PGD2 between murine myofibroblasts and alternatively activated macrophages enhances anti-inflammatory phenotype in both cells

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Alternatively activated macrophages (AAMs) are important cells in the resolution of inflammation and tissue repair. We examined the impact of myofibroblasts, a vital cell in wound healing and tissue repair, on the development and function of AAMs.


The interaction between AAMs and myofibroblasts was tested using conditioned medium from murine dermal myofibroblasts and bone marrow-derived macrophages. AAMs were differentiated with IL-4 and IL-13.


Conditioned medium from myofibroblasts enhanced the expression of AAM markers, arginase 1 and Ym1 (chitinase-3-like 3) and the spontaneous production of IL-10, while suppressing LPS-induced nitric oxide production. IL-6 from the myofibroblasts contributed to the amplification of the AAM phenotype; the selective COX-2 inhibitor, NS-398, significantly reduced the ability of myofibroblasts to promote an AAM phenotype. Pharmacological analyses indicated that myofibroblast-derived IL-6 enhanced arginase activity and spontaneous IL-10 output, while PGE2, via the EP4 receptor, enhanced arginase expression and LPS-evoked IL-10 production. PGD2 suppressed LPS-evoked nitric oxide via the DP1 receptor. Reciprocally, conditioned medium from macrophages treated with IL-4 + IL-13 and myofibroblast conditioned medium components, but not macrophages given IL-4 + IL-13 only, reduced myofibroblast migration, the expression of COX-2, and the production of PGE2 and PGD2.


These findings define mechanisms by which myofibroblasts enhance an AAM phenotype, which can promote wound healing directly, and/or via feedback communication to the myofibroblast, subsequently down-regulating its capacity to promote AAM function. This is an important homeostatic regulatory pathway in wound healing that can also limit unwanted fibrosis.

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