Abstract
Intestinal macrophages are highly mobile cells with extraordinary plasticity and actively contribute to cytokine-mediated epithelial cell damage. The mechanisms triggering macrophage polarization into a proinflammatory phenotype are unknown. Here, we report that during inflammation macrophages enhance its intercellular adhesion properties in order to acquire a M1-phenotype. Using in vitro and in vivo models we demonstrate that intercellular adhesion is mediated by integrin-αVβ3 and relies in the presence of the unconventional class I myosin 1F (Myo1F). Intercellular adhesion mediated by αVβ3 stimulates M1-like phenotype in macrophages through hyperactivation of STAT1 and STAT3 downstream of ILK/Akt/mTOR signaling. Inhibition of integrin-αVβ3, Akt/mTOR, or lack of Myo1F attenuated the commitment of macrophages into a pro-inflammatory phenotype. In a model of colitis, Myo1F deficiency strongly reduces the secretion of proinflammatory cytokines, decreases epithelial damage, ameliorates disease activity, and enhances tissue repair. Together our findings uncover an unknown role for Myo1F as part of the machinery that regulates intercellular adhesion and polarization in macrophages.
Highlights
Mucosal macrophages play an important role in tissue remodeling, homeostasis, and repair [1, 2]
We showed that myosin 1F (Myo1F) expressed in inflammatory macrophages in the colonic mucosa of colitic mice stimulates the production and secretion of IL-1β via stimulation of Akt and STAT signaling
In the absence of Myo1F the production of IL-1β by macrophages decreased in the mucosa of colitic mice and this process resulted in accelerated epithelial injury reparation
Summary
Mucosal macrophages play an important role in tissue remodeling, homeostasis, and repair [1, 2]. M1-macrophage commitment induced by IFN-γ, requires the expression of a specific pool of genes associated with the activation of STAT1 [6,7,8]. STAT3 activation downstream of IL-10r/JAK1 has been linked to the so called M2 phenotype and the repression of TNF-α, IL-1β, IL-12, and IFN-γ [9]. In addition to STAT signaling, phosphoinositide 3-kinase (PI3K) stimulation is crucial for macrophage polarization [10]. At the inflammation site multiple simultaneous signals are Myosin 1F Stimulates M1-Phenotype in Macrophages released, the acquisition of the specialized phenotype displayed by macrophages requires a dynamic response to a specific combination of environmental factors [12, 13]. Identifying the machinery responsible for the integration of those inputs is highly relevant for understanding macrophage polarization and physiology
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