Fib
rin is a major component of the provisional extracellular mat
rix formed du
ring tissue repair following injury, and enables cell infiltration and ancho
ring at the wound site. Macrophages are dynamic regulators of this process, advancing and resolving inflammation in response to cues in their microenvironment. Although much is known about how soluble factors such as cytokines and chemokines regulate macrophage pola
rization, less is understood about how insoluble and adhesive cues, specifically the blood coagulation mat
rix fib
rin, influence macrophage behavior. In this study, we observed that fib
rin and its precursor fib
rinogen elicit distinct macrophage functions. Cultu
ring macrophages on fib
rin gels fab
ricated by combining fib
rinogen with thrombin stimulated secretion of the anti-inflammatory cytokine, interleukin-10 (IL-10). In contrast, exposure of macrophages to soluble fib
rinogen stimulated high levels of inflammatory cytokine tumor necrosis factor alpha (
TNF-α). Macrophages maintained their anti-inflammatory behavior when cultured on fib
rin gels in the presence of soluble fib
rinogen. In addition, adhesion to fib
rin mat
rices inhibited TNF-α production in response to stimulation with LPS and IFN-γ, cytokines known to promote inflammatory macrophage pola
rization. Our data demonstrate that fib
rin exerts a protective effect on macrophages, preventing inflammatory activation by stimuli including fib
rinogen, LPS, and IFN-γ. Together, our study suggests that the presentation of fib
rin(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.