Formyl peptide receptor 2 is regulated by RNA mimics and viruses through an IFN-ß-STAT3-dependent pathway.

The regulation of host factors is a key strategy employed by viruses to suppress host defense systems and enhance their propagation; however, the mechanisms that underlie this regulation is still unclear. Formyl peptide receptor 2 (FPR2) recognizes numerous proinflammatory and anti-inflammatory stimuli, and emerging reports indicate elevated levels of FPR2 in several disease conditions. Although studies have implicated FPR2 in a myriad of inflammatory conditions, how viruses exploit this cell-surface receptor to facilitate disease progression remains unknown. In this study, we show that the activation of TLR3 and TLR7 induces the up-regulation of FPR2. We provide evidence that signal transducer and activator of transcription 3 (STAT3) phosphorylation is critical for the induction of FPR2 by double-stranded RNA, but not single-stranded RNA viral mimetics. Use of bone marrow-derived macrophages (BMDMs) from IFN-αß receptor-deficient mice revealed that signaling via the type I IFN-STAT3 pathway is essential for FPR2 induction. We demonstrate that virus infection with enterovirus 71 and H1N1 PR8 influenza virus results in increased FPR2 expression. Inhibition of STAT3 phosphorylation in virus-infected cells repressed the induction of FPR2, which led to a reduction in viral loads. Finally, the absence of FPR2 in murine BMDMs resulted in lower viral loads, which suggests that FPR2 may be important for virus replication. Altogether, our study provides novel insights into how RNA viruses may hijack the immune system to facilitate their replication and survival. Identification of these regulatory elements may be useful in designing therapeutics for inflammatory disease conditions that are associated with elevated levels of FPR2.-Ampomah, P. B., Moraes, L. A., Lukman, H. M., Lim, L. H. K. Formyl peptide receptor 2 is regulated by RNA mimics and viruses through an IFN-ß-STAT3-dependent pathway.

Annexin-A1 enhances breast cancer growth and migration by promoting alternative macrophage polarization in the tumour microenvironment.

Macrophages are potent immune cells with well-established roles in the response to stress, injury, infection and inflammation. The classically activated macrophages (M1) are induced by lipopolysaccharide (LPS) and express a wide range of pro-inflammatory genes. M2 macrophages are induced by T helper type 2 cytokines such as interleukin-4 (IL4) and express high levels of anti-inflammatory and tissue repair genes. The strong association between macrophages and tumour cells as well as the high incidences of leukocyte infiltration in solid tumours have contributed to the discovery that tumour-associated macrophages (TAMs) are key to tumour progression. Here, we investigated the role of Annexin A1 (ANXA1), a well characterized immunomodulatory protein on macrophage polarization and the interaction between macrophages and breast cancer cells. Our results demonstrate that ANXA1 regulates macrophage polarization and activation. ANXA1 can act dually as an endogenous signalling molecule or as a secreted mediator which acts via its receptor, FPR2, to promote macrophage polarization. Furthermore, ANXA1 deficient mice exhibit reduced tumour growth and enhanced survival in vivo, possibly due to increased M1 macrophages within the tumor microenvironment. These results provide new insights into the molecular mechanisms of macrophage polarization with therapeutic potential to suppress breast cancer growth and metastasis.