Figure 2: Manipulation of macrophage polarisation: the future? Macrophage polarisation, plasticity and effector phenotype can be determined by the manipulation of differentiation, activation and suppression/tolerogenic signals. Such harnessing of Mφ effector phenotypes may prove beneficial to the future treatment of both inflammatory mucosal diseases such as CP and CD and immune suppressive mucosal diseases such as OSCC. Mφ polarisation can be manipulated or initiated towards the pro-inflammatory, anti-tumour M1 subset (yellow box and red arrows) by a range of receptors, which include GM-CSF-R, IFNγ-R and TLR activation (middle blue box) and signalling intermediates such as STAT-1, p65 NF-κB and SOCS3. Conversely, the polarisation towards the anti-inflammatory, pro-tumour M2 subset is indicated by the white box and green arrows. M2 polarisation can be initiated by the receptors to the Th2-derived cytokines, IL-4/IL-13, M-CSF-R, FcγRs as well as IL-10R and the TGFβR (not indicated on figure). The signalling intermediates associated with M2 Mφs include STAT3, STAT6, PI3K and p50 NF-κB. Cross-regulation is indicated by inhibitory (blunted) lines, which are coloured purple to indicate M2 suppression of M1 polarisation (by STAT6, Tpl2, PI3K, p50 NF-κB and the cAMP-modulated C/EBPβ) and red to indicate M1 suppression of M2 polarisation (by STAT1, p65 NF-κB and the ITIM-recruited phosphatase (P-ase), SHIP1). In addition, Mφ activation/polarisation signals can be suppressed by a variety of exogenous and endogenous negative regulators, described in ET mechanisms. These include signal suppression by SHIP1 through ligation of siglecs 3-10 and FcγRIIb and ligation of the negative regulatory receptors, CD200R and SIRP1α. PI3K has been suggested to polarise towards the M2 subset, activation of its endogenous negative phosphatase regulator, PTEN, will indirectly bias polarisation towards M1 Mφs. Finally, activation of Mφ function by TLRs can be suppressed by inhibiting adaptor protein association and transduction of signals to TRAF6 and downstream effectors such as NF-κB and MAPKs via membrane-associated exogenous signalling through SIGIRR, ST-2, FcγRIIb, Siglecs, CD200R, SIRP1α and endogenous-associated negative regulation through IL-10-induced SOCS3. Further investigation regarding the fine balance between signals transduced through CD16 (FcγRIII) and CD32 (FcγRIIb) may highlight the contribution of the different monocyte subsets (described by their high or low expression of CD16) to M1/M2 polarisation.