Regulation of adaptive immunity by innate immune cells is widely accepted. Conversely, adaptive immune cells can also regulate cells of the innate immune system. Here, we report for the first time the essential role of B cells in regulating macrophage (M/) phenotype. In vitro B cell/M/ co-culture experiments together with experiments in transgenic mice models for B-cell deficiency or overexpression showed B1 cells to polarize M/ to a distinct phenotype. This was characterized by downregulated TNF-a, IL-1b and CCL3, but upregulated IL-10 upon LPS stimulation; constitutive expression of M2 M/ markers (e.g. Ym1, Fizz1) and overexpression of TRIF-dependent cytokines (IFN-b, CCL5). Mechanistically, this phenotype was linked to a defective NF-jB activation, but a functional TRIF/STAT1 pathway. B1-cell-derived IL-10 was found to be instrumental in the polarization of these M/. Finally, in vivo relevance of B1-cell-induced M/ polarization was confirmed using the B16 melanoma tumor model where adoptive transfer of B1 cells induced an M2 polarization of tumor-associated M/. Collectively, our results define a new mechanism of M/ polarization wherein B1 cells play a key role in driving M/ to a unique, but M2-biased phenotype. Future studies along these lines may lead to targeting of B1 cells to regulate M/ response in inflammation and cancer.
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IntroductionMacrophages (Mf) are a heterogeneous cell population involved in diverse physiological processes including anti-microbial defence, wound resolution, inflammation, tissue remodeling, plaque formation in atherosclerosis and promotion of tumor growth [1][2][3][4][5][6][7]. Despite their heterogeneity, Mf can be broadly divided into M1 (classically activated) or M2 (alternatively activated) phenotypes [1,[8][9][10][11][12]. The M1 phenotype is induced in response to microbial products such as LPS or proinflammatory cytokines including IFN-g, IL-1b or TNF-a. M1 Mf produce further proinflammatory cytokines (TNF-a, IL-12 and CCL3) with reactive oxygen and nitrogen intermediates, which combine to give M1 Mf potent antimicrobial, tumoricidal and inflammatory properties [12]. In contrast, the M2 phenotype results from exposure to antiinflammatory molecules such as glucocorticoid hormones, IL-4, Ã These authors contributed equally to this work.
2296IL-13, IL-10 or immune complexes [10][11][12]. M2 Mf are antiinflammatory and immunosuppressive in nature. They are highly phagocytic, preferentially activate the arginase pathway, promote angiogenesis, tissue remodeling and have pro-tumoral activity [8,12]. However, in vivo, the division between M1 and M2 cells may be blurred, with the above phenotypes likely representing two extremes in a continuum of Mf functional states [9,[13][14][15].Transcriptome data demonstrate the existence of distinct polarization phenotypes for Mf associated with specific pathological conditions [4,7,[16][17][18]. Based on this, it is believed that the phenotype of an Mf is a reflection of its immediate microenvironment....