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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.

Efferocytosis, the clearance of apoptotic cells (ACs) by macrophages, is critical for tissue resolution, with defects driving many diseases. Mechanisms of efferocytosis-mediated resolution are incompletely understood. Here, we show that AC-derived methionine regulates resolution through epigenetic repression of the ERK1/2 phosphatase Dusp4. We focus on two key efferocytosis-induced pro-resolving mediators, PGE2 and TGFβ1, and show that efferocytosis induces Ptgs2/COX2, leading to PGE2 synthesis and PGE2-mediated induction of TGFβ1. ERK1/2 phosphorylation/activation by AC-activated CD36 is necessary for Ptgs2 induction, but this is insufficient owing to an ERK-DUSP4 negative-feedback pathway that lowers phospho-ERK. However, subsequent AC engulfment and phagolysosomal degradation repress Dusp4, enabling enhanced phospho-ERK and induction of the Ptgs2-PGE2-TGFβ1 pathway. Mechanistically, AC-derived methionine is converted to S-adenosylmethionine (SAM), which is used by DNA-methyltransferase-3A (DNMT3A) to methylate Dusp4. Bone-marrow DNMT3A deletion in mice blocks COX2/PGE2, TGFβ1, and resolution in sterile-peritonitis, apoptosis-induced thymus injury, and atherosclerosis. Knowledge of how macrophages use AC-cargo and epigenetics to induce resolution provides mechanistic insight and therapeutic options for diseases driven by impaired resolution.

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