Macrophage polarization to a unique phenotype driven by B cells

Abstract

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. Supporting Information available online 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....

Convergent pathways of macrophage polarization: The role of B cells

“…Binding of B1-cell-derived IgM to macrophages unexpectedly resulted in a marked reduction of prototypical M2 genes (e.g. Ym1, Fizz1 and Mgl2) [17]. Interestingly, inhibition of IL-10, which is constitutively express by B1 cells, prevented B1-cellinduced M2-polarization of macrophages [17], indicating the crucial role of this cytokine in tuning cancer-related inflammatory programs.…”

“…In some cases, natural antibodies produced by B1b cells have been shown to have the potential to react with self-antigens leading to autoimmunity. On the other hand, CD5 1 B1a cells have also been shown to play an inhibitory role in the immune response, particularly during inflammation/infection and in cancer, mainly sustained by the production of .In this issue of the European Journal of Immunology, using an in vitro B-cell/macrophage co-culture system, together with experiments in transgenic mice models of B-cell deficiency or overexpression, Wong et al [17] suggest that B1 cells, but not B2 cells, polarize peritoneal macrophages to a phenotype characterized by impaired expression of LPS-induced pro-inflammatory genes (e.g. Tnfa, Ccl3 and Il1b), with upregulation of the anti-inflammatory gene Il10.…”

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

“…In a transplanted mammary carcinoma, complement was shown to be involved in myelomonocytic cell recruitment [34], although the mechanisms responsible for complement activation in tumors remain to be defined. It should be noted that B cells can use tools other than antibodies to skew macrophage function and promote tumor progression, including IL-10 and lymphotoxin (LT) [35][36][37][38], and B regulatory cells may be well suited for this [38]. Thus, the mechanisms of co-opting the function of myelomonocytic cells in tumors can differ considerably, although M2-like skewing is a recurrent common denominator.…”

“…Thus, the interaction of macrophages in different states of activation with antibodies and more generally with B cells is contextdependent and can result in promotion of carcinogenesis (e.g. [33,35,38,47]) or anti-tumor activity [3].…”

Macrophage heterogeneity and acute inflammation

“…Tissueresident macrophages play a crucial role in normal tissue homeostasis, helping to maintain the status quo and coordinate responses to homeostatic cues. In the peritoneal cavity, for example, tissueresident macrophages are major sources of CXCL13, a chemokine involved in the homing of peritoneal B-cell populations [8], but are, themselves, regulated by the peritoneal B cells [9].…”