Figure 9. A functional scheme for macrophage phenotype conversions during resolution-phase efferocytosis.

A macrophage that infiltrated an inflamed tissue adopts an M1-like phenotype (including expression of inflammatory cytokines and chemokines, iNOS, and COX 2 [1]) previous to encounter with apoptotic PMNs (A). Once it encounters apoptotic PMN and starts to engulf them, the macrophage switches to an M2-like phenotype that is involved in tissue repair and return to homeostasis. This switch is accompanied by an increase in the expression of arginase-1 and IL-10, whereas a decrease in the expression of pro-inflammatory cytokines, as well as COX-2, and iNOS also takes place (B). Reports documenting a role for M2 cytokines in the resolution of inflammation and efferocytosis [42, 43] seem to support this part of our scheme. As the engulfment of apoptotic PMN by the macrophage continues and reaches a threshold level (satiating efferocytosis) the macrophage undergoes another switch to the CD11b^low phenotype (C) that secretes neither pro-inflammatory cytokines and chemokines nor IL-10, but does secret higher levels of TGFβ. CD11b^low macrophages also do not express iNOS or arginase-1, and express only low levels of COX-2. Interestingly, this switch leads to the expression of 12/15-LO, which is exclusively expressed by CD11b^low macrophages and was previously reported to be expressed in a TGFβ-dependent manner following the interaction of macrophages with apoptotic cells [19]. The second phenotype switch also seems to stop CD18/CD11b-mediated apoptotic PMN engulfment [8, 12] thereby allowing rapid macrophage departure of the resolving tissue and emigration to lymphoid organs. At these target organs CD11b^low macrophages presumably produce 12/15-LO-derived pro-resolving lipid mediators, and deliver homeostatic signals to antigen presenting cells and lymphocytes [34, 44]. Satiating efferocytosis can be modulated by pro-resolving mediators, such as RvD1, RvE1, and Dex (D). This modulation enhances the immune-silencing and departure of pro-resolving CD11b^low macrophages to the lymphatics, where they can contribute to the termination of the acquired immune response. RvE1 and Dex also promote the infiltration of new macrophages to the resolving tissue to continue the necessary clearance of apoptotic PMN and return to homeostasis.