Loss of SHP2 skews macrophage differentiation to M2 phenotype and abates its phagocytic activity in response to poly(I:C) and S aureus dual stimulation. The peritoneal macrophages from Shpfl/fl and LysMCre:Shp2fl/fl mice were stimulated with poly(I:C) (20 μg/mL) for 24 h and then incubated with S aureus (MOI, 10) for 3, 6 and 12 h, respectively. (A‐D) Expression of M1 gene marker including IL‐6, TNF‐α, IL‐12b and iNOS was measured by qPCR. (E‐G) Expression of M2 gene markers (eg, Arg‐1, YM‐1 and Fizz1) was determined by qPCR. *P < .05, **P < .01. (H) After pre‐stimulation by poly(I:C) (20 μg/mL) for 24 h, the PMs were incubated with FITC‐labelled bacteria for 1 and 2 h. Then, the fluorescence positivity was analysed by flow cytometry. Representative traces of bacteria engulfed were shown by red (Shpfl/fl) and blue line (LysMCre:Shp2fl/fl), respectively. Data are representative of 3 independent experiments