title: Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization.
abstract: Suppressors of cytokine signaling (SOCS) are important regulators of lipopolysaccharide (LPS) and cytokine responses but their role in macrophage polarization is unknown. We have shown here that myeloid-restricted Socs3 deletion (Socs3(Lyz2cre)) resulted in resistance to LPS-induced endotoxic shock, whereas Socs2(-/-) mice were highly susceptible. We observed striking bias toward M2-like macrophages in Socs3(Lyz2cre) mice, whereas the M1-like population was enriched in Socs2(-/-) mice. Adoptive transfer experiments showed that responses to endotoxic shock and polymicrobial sepsis were transferable and macrophage dependent. Critically, this dichotomous response was associated with enhanced regulatory T (Treg) cell recruitment by Socs3(Lyz2cre) cells, whereas Treg cell recruitment was absent in the presence of Socs2(-/-) macrophages. In addition, altered polarization coincided with enhanced interferon-gamma (IFN-γ)-induced signal transducer and activator of transcription-1 (STAT1) activation in Socs2(-/-) macrophages and enhanced interleukin-4 (IL-4) plus IL-13-induced STAT6 phosphorylation in Socs3(Lyz2cre) macrophages. SOCS, therefore, are essential controllers of macrophage polarization, regulating inflammatory responses.
authors.affiliation: Centre for Infection and Immunity, School of Medicine Dentistry and Biomedical Sciences, Queen's University, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Spence
authors.forename: Amy
authors.initials: A
authors.lastname: Fitzsimons
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Boyd
authors.forename: Julia
authors.initials: J
authors.lastname: Kessler
authors.forename: Denise
authors.initials: D
authors.lastname: Fitzgerald
authors.forename: Joanne
authors.initials: J
authors.lastname: Elliott
authors.forename: Joan Ní
authors.initials: JN
authors.lastname: Gabhann
authors.forename: Siobhan
authors.initials: S
authors.lastname: Smith
authors.forename: Antonio
authors.initials: A
authors.lastname: Sica
authors.forename: Emily
authors.initials: E
authors.lastname: Hams
authors.forename: Sean P
authors.initials: SP
authors.lastname: Saunders
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Jefferies
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Danny F
authors.initials: DF
authors.lastname: McAuley
authors.forename: Adrien
authors.initials: A
authors.lastname: Kissenpfennig
authors.forename: James A
authors.initials: JA
authors.lastname: Johnston
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D051379:Mice; D050791:STAT Transcription Factors / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014185:Transplantation, Isogeneic
chemical_list: D050791:STAT Transcription Factors; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10