The CD20 homolog Ms4a8a integrates pro‐ and anti‐inflammatory signals in novel M2‐like macrophages and is expressed in parasite infection

Abstract

Recently, we identified the CD20 homolog Ms4a8a as a novel molecule expressed by tumor-associated macrophages that directly enhances tumor growth. Here, we analyzed Ms4a8a + macrophages in M2-associated infectious pathologies. In late-stage Trypanosoma congolense and Taenia crassiceps infections, Ms4a8a expression was detected in hepatic and peritoneal macrophages respectively. Innate immunity in these infections is modulated by Toll-like receptor (TLR) signaling and TLR2/4/7 agonists strongly induced Ms4a8a expression in bone marrow derived macrophages (BMDMs) treated with M2 mediators (glucocorticoids/IL-4). LPS/dexamethasone/IL-4-induced Ms4a8a + BMDMs were characterized by strong expression of mRNA of mannose receptor (Mmr), arginase 1, and CD163, and by decreased iNOS expression. Coinduction of Ms4a8a by M2 mediators and TLR agonists involved the classical TLR signaling cascade via activation of MyD88/TRIF and NF-κB. Forced overexpression of Ms4a8a modulated the TLR4 response of RAW264.7 cells as shown by gene expression profiling. Upregulation of Hdc, Tcfec, and Sla was confirmed both in primary LPS/dexamethasone/IL-4-stimulated Ms4a8a + BMDMs and in peritoneal macrophages from late-stage Taenia crassiceps infection. In conclusion, we show that TLR signaling skews the typical alternative macrophage activation program to induce a special M2-like macrophage subset in vitro that also occurs in immunomodulatory immune reactions in vivo, a process directly involving the CD20 homolog Ms4a8a. Eur. J. Immunol. 2012Immunol. . 42: 2971Immunol. -2982 IntroductionMacrophages have an extraordinary ability to rapidly adapt to new environmental stimuli by altering their gene expression profile and functions [1]. These enormous variations enable macrophages to participate in different biological and pathological processes such as the maintenance of tissue homeostasis, orchestration of defense responses, and healing processes in tissues. The phenotypic plasticity and functional heterogeneity of macrophages renders their classification difficult. Thus, a simplified approach was put forward in analogy to the Th1/Th2 dichotomy [2,3]. Accordingly, M1 or classically activated macrophages differentiate from monocytes under the predominant influence of pro-inflammatory cytokines such as IFN-γ, IL-12, or TNF-α, while M2, or alternative, macrophage activation was primarily described as a response to Th2 cytokines such as IL-4, IL-13, and IL-10, as well as to anti-inflammatory mediators such as glucocorticoids (GCs) [4][5][6][7]. As these macrophage phenotypes influence the tissue environment, for example, via secretion of active mediators, a solid characterization of macrophages, especially in pathological processes such as cancer or chronic inflammation, is needed to uncover unique key cellular regulators [8].In a previous study, the CD20 homolog Ms4a8a was found to be expressed by M2-like tumor-associated macrophages (TAMs) in murine mammary carcinoma and malignant melanoma [9]. For the induction of Ms4a8a expression in these ...

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Clinical significance of sCD163 and its possible role in asthma

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MS4A8B promotes cell proliferation in prostate cancer

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