Suppressors of cytokine signalling (SOCS) 2 and 3 diametrically control macrophage polarisation

Suppressors of cytokine signalling (SOCS) 2 and 3 diametrically control macrophage polarisation S. Spence,* A. Fitzsimons,* C. Boyd,* J. Kessler,* D. Fitzgerald,* J. Elliott,* J. Ni Gabhann, S. Smith, A. Sica, E. Hams,§ S. P. Saunders,§ C. Jefferies, P. Fallon,§ D. Mcauley,* A. Kissenpfennig* & J. Johnston* *Queen’s University Belfast, Belfast, UK, Royal College of Surgeons in Ireland, Dubin, Ireland, Instituto Clinca Humanitas, Milan, Italy, §Trinity College Dublin, Dublin, Ireland M1 macrophages, induced by pro-inflammatory stimuli, and involved in the acute response. M2 macrophages are polarised by anti-inflammatory stimuli and mainly involved in healing. The Suppressors of cytokine signalling (SOCS) are important regulators of both LPS and cytokine responses but their role in macrophage polarisation is unknown. Myeloid restricted SOCS3 deletion (SOCS3LysMcre) resulted in profound resistance to endotoxic shock, whereas SOCS2)/) mice were highly susceptible. This was associated with striking bias towards M2-like macrophages in SOCS3LysMcre mice, whereas the M1-like population was enriched in SOCS2)/) mice. Through adoptive transfer experiments we show that these antipodal responses to endotoxic shock and to polymicrobial sepsis (caecal ligation puncture) were both transferable and entirely macrophage-dependent. Critically this dichotomous response was associated with enhanced T-reg recruitment by SOCS3)/) cells, yet in the presence of SOCS2)/) macrophages, Foxp3+ T cells were completely absent at the inflammatory site. The altered polarisation coincided with enhanced IFNc- induced STAT1 in SOCS2)/) macrophages and enhanced IL-4/ IL-13 induced STAT6 phosphorylation in SOCS3)/) cells corresponding to altered binding to traditional gene markers of M1 and M2 macrophages (iNOS, TNFa, ARG-1 and CCL-17,). In the absence of SOCS2, macrophages seem unable to elicit an anti- inflammatory response even when stimulated with typical M2 stimulus (IL-4/IL-13, IL- 10), whilst the absence of SOCS3 prevents a pro-inflammatory response even in the presence of LPS/IFNc. Interestingly, the polarisation of macrophages in the absence of SOCS2 or SOCS3 seems fixed and irreversible. Therefore SOCS are essential controllers of macrophage polarisation and regulate the inflammatory response.