Fibrin is a major component o
f the provisional extracellular matrix
formed during tissue repair
following injury, and enables cell in
filtration and anchoring at the wound site. Macrophages are dynamic regulators o
f this process, advancing and resolving in
flammation in response to cues in their microenvironment. Although much is known about how soluble
factors such as cytokines and chemokines regulate macrophage polarization, less is understood about how insoluble and adhesive cues, speci
fically the blood coagulation matrix
fibrin, in
fluence macrophage behavior. In this study, we observed that
fibrin and its precursor
fibrinogen elicit distinct macrophage
functions. Culturing macrophages on
fibrin gels
fabricated by combining
fibrinogen with thrombin stimulated secretion o
f the anti-in
flammatory cytokine, interleukin-10 (IL-10). In contrast, exposure o
f macrophages to soluble
fibrinogen stimulated high levels o
f in
flammatory cytokine tumor necrosis
factor alpha (TNF-α). Macrophages maintained their anti-in
flammatory behavior when cultured on
fibrin gels in the presence o
f soluble
fibrinogen. In addition, adhesion to
fibrin matrices inhibited TNF-α production in response to stimulation with LPS and IFN-γ, cytokines known to promote in
flammatory macrophage polarization. Our data demonstrate that
fibrin exerts a protective e
ffect on macrophages, preventing in
flammatory activation by stimuli including
fibrinogen, LPS, and IFN-γ. Together, our study suggests that the presentation o
f fibrin(ogen) may be a key switch in regulating macrophage phenotype behavior, and this
feature may provide a valuable immunomodulatory strategy
for tissue healing and regeneration.
Statement of Significance
Fibrin is a fibrous protein resulting from blood clotting and provides a provisional matrix into which cells migrate and to which they adhere during wound healing. Macrophages play an important role in this process, and are needed for both advancing and resolving inflammation. We demonstrate that culture of macrophages on fibrin matrices exerts an anti-inflammatory effect, whereas the soluble precursor fibrinogen stimulates inflammatory activation. Moreover, culture on fibrin completely abrogates inflammatory signaling caused by fibrinogen or known inflammatory stimuli including LPS and IFN-γ. Together, these studies show that the presentation of fibrin(ogen) is important for regulating a switch between macrophage pro- and anti-inflammatory behavior.
