Autocrine GABA signaling distinctively regulates phenotypic activation of mouse pulmonary macrophages

Abstract

In response to micro-environmental cues such as microbial infections or T-helper 1 and 2 (T_H1 and T_H2) cytokines, macrophages (Mϕs) develop into M1- or M2-like phenotypes. Phenotypic polarization/activation of Mϕs are also essentially regulated by autocrine signals. Type-A γ-aminobutyric acid receptor (GABA_AR)-mediated autocrine signaling is critical for phenotypic differentiation and transformation of various cell types. The present study explored whether GABA_AR signaling regulates lung Mϕ (LMϕ) phenotypic activation under M1/T_H1 and M2/T_H2 environments. Results showed that GABA_AR subunits were expressed by primary LMϕ of mice and the mouse Mϕ cell line RAW264.7. The expression levels of GABA_AR subunits in mouse LMϕs and RAW264.7 cells decreased or increased concurrently with classical (M1) or alternative (M2) activation, respectively. Moreover, activation or blockade of GABA_ARs distinctively influenced the phenotypic characteristics of Mϕ. These results suggested that microenvironments leading to LMϕ phenotypic polarization concurrently modulates autocrine GABA signaling and its role in Mϕ activation.

Keywords: Arginase-1; Inducible nitric oxide synthase; Interleukin-4; Lung; Macrophage polarization; Mouse; Tumor necrosis factor alpha; Type-A γ-aminobutyric acid receptor.