Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.

Alternative activation of macrophages plays an important role in a range of physiological and pathological processes. This alternative phenotype, also known as M2 macrophages, is induced by type 2 cytokines such as IL-4. The binding of IL-4 to its receptor leads to activation of two major signaling pathways: STAT-6 and PI3K. However, recent studies have described that p38 MAPK might play a role in IL-4-dependent signaling in some cells, although its role in macrophages is still controversial. In this study, we investigated whether p38 MAPK plays a role in the polarization of macrophages in mice. Our results reveal that IL-4 induces phosphorylation of p38 MAPK in thioglycollate-elicited murine peritoneal macrophages, in addition to STAT-6 and PI3K activation. Furthermore, p38 MAPK inactivation, by gene silencing or pharmacological inhibition, suppressed IL-4-induced typical M2 markers, indicating the involvement of p38 MAPK in the signaling of IL-4 leading to M2-macrophage polarization. Moreover, p38 MAPK inhibition blocked phosphorylation of STAT-6 and Akt, suggesting that p38 MAPK is upstream of these signaling pathways. Finally, we show that in an in vivo model of chitin-induced M2 polarization, p38 MAPK inhibition also diminished activation of M2 markers. Taken together, our data establish a new role for p38 MAPK during IL-4-induced alternative activation of macrophages.Keywords: Alternative activation r Chitin r IL-4 r JAK/STAT r Macrophages r p38 MAPK Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages represent an essential cell population of innate immunity that plays a critical role in inflammation and host defense as well as in the maintenance of tissue homeostasis [1]. Two major macrophage phenotypes have been characterized according to the activation by different microenvironmental signals: the classically activated macrophages (M1) and the alternatively activated macrophages (M2) [1,2]. M1 macrophages Correspondence: Dr. Sonsoles Hortelano e-mail: shortelano@isciii.es develop in response to proinflammatory stimuli like IFN-γ or IL-1β and bacterial products such as LPS. This phenotype has antimicrobial and cytotoxic functions and is characterized by enhanced production of proinflammatory cytokines, expression of MHC class II molecules, and generation of free radicals including nitric oxide (NO). In contrast, M2 macrophages differentiate in the presence of cytokines as IL-4 or IL-13. They have enhanced capacity for endocytosis but reduced motility and cytotoxic effects, showing both anti-inflammatory activities and a tissue-repair function. In addition, these M2 macrophages express a different subset of innate immunity molecules as compared to M1 macrophages [3,4]. Expression of arginase-1 (Arg-1), the mannose receptor (MR), and genes involved in tissue remodeling such as chitinase 3-like 3 C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 274Lidia Jiménez-Garcia et al. Eur. J. Immunol. 2015. 45: 27...

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