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A mechanistic integrative computational model of macrophage polarization: Implications in human pathophysiology

Fig 5

Pathway feedbacks and cross-talks in M1-M2 regulatory network.

Overexpression of SOCS1 and SOCS3 in macrophages can downregulate activation of (A) STAT1 by IFN-γ and (B) STAT6 by IL-4. Silencing of SOCS3 promotes (C) IFN-γ-induced M1 marker expression while it minimally affects (D) IL-4-induced M2 marker expression (relative fold changes are labeled). (A-D) Overexpression is modeled as 50x initial level with normal (1x) production, and silencing is modeled as 0 initial level with 0 production. (E) Simulated dose response of iNOS and Arg-1; relative protein levels measured at 12 h are plotted and labeled (the baseline condition is represented by the 0.01 ng/ml case). (F) Upon IFN-γ stimulation followed by the addition of IL-4 (at 4 h), cellular IRF-1 level is downregulated compared to IFN-γ only; (G) Upon IL-4 stimulation followed by the addition of IFN-γ (at 1 hr), cellular activation of AKT is downregulated compared to IL-4 only. (H) The addition of a second stimulus IFN-γ (after 24 h of IL-4 stimulation) would antagonize the expression pattern of M1 and M2 markers induced by IL-4 (see also S5G Fig). (I) Similarly, IL-4 added after 24 h of IFN-γ stimulation would antagonize the marker expression pattern induced by IFN-γ. When macrophages are stimulated with IFN-γ and IL-4 simultaneously, the simulated expression of (J) M1 and M2 markers as well as (K) the activation of a number of M1 and M2 signature proteins (see also S5I Fig) are collectively induced with distinct temporal profiles. (L) Dynamic protein expression patterns (after 12, 24 and 48 h of stimulation) of M1 and M2 markers in macrophages under seven different stimulation conditions (A+B means simultaneous stimulation, expression levels are normalized to the untreated/time 0 levels and then log2 transformed). (A-L) All simulation results are protein levels (except CXCL10 is mRNA level). (C-E, H-K) Y-axes show relative expression respectively (C-D, H-K: normalized to untreated/control/time 0 levels; E: normalized to maximum levels at 50 ng/ml). Simulated treatment doses are 10 ng/ml IFN-γ and 10 ng/ml IL-4 for (A-D), 10 ng/ml IFN-γ and 20 ng/ml IL-4 for (F-G), 20 ng/ml IFN-γ and 20 ng/ml IL-4 for (H-I), 10 ng/ml IFN-γ and 5 ng/ml IL-4 for (J-L). Utr–untreated, hyp–hypoxia (2% oxygen for L).

Fig 5

doi: https://doi.org/10.1371/journal.pcbi.1007468.g005