Suppressors of Cytokine Signalling (SOCS) 1 and SOCS3 coordinate regulation of macrophage polarization — ASN Events
  1. Schedule
  2. Poster Session 1
  3. Suppressors of Cytokine Signalling (SOCS) 1 and SOCS3 coordinate regulation of macrophage polarization

Suppressors of Cytokine Signalling (SOCS) 1 and SOCS3 coordinate regulation of macrophage polarization (#281)

Tatiana B Kolesnik 1 , Takashi Ushiki 1 , Edmond Linossi 1 2 , Jian-Guo Zhang 1 2 , Nikos A Nicola 1 2 , Peter J Murray 3 , Warren S Alexander 1 2 , Sandra A Nicholson 1 2
  1. The Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  3. Department of Infectious Diseases and Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Macrophages are multi-functional innate immune cells, which play a critical role in the host defence against various pathogens such as bacteria, viruses and parasites.  Once activated, they produce cytokines and chemokines to promote cell recruitment and proliferation, tissue repair and wound healing.  They display a high degree of heterogeneity and phenotypic plasticity depending on their origin, the detection of pathogen-associated molecular pattern molecules (PAMPs) and the surrounding cytokine milieu. At present macrophages are broadly classified into M1 (classically activated) and M2 (alternatively activated), based on the activating stimuli and corresponding expression of signature markers. The SOCS family proteins (CIS and SOCS1-7) play an important role in the negative regulation of JAK-STAT signalling in various cytokine pathways. Genetic deletion of either Socs1 or Socs3 has a dramatic effect, resulting in excessive cytokine-driven inflammation. In order to address the possible redundancy between SOCS1 and SOCS3 in regulating macrophage polarization, we have generated CSF-1-cultured bone marrow-derived macrophages deficient in SOCS1, SOCS3 or both SOCS1 and SOCS3, and polarized them in the presence of interferon (IFN)γ (M1), interleukin (IL)-4 (M2) or lipopolysaccharide (LPS). Analysis of M1/M2 markers confirmed that SOCS1 is a negative regulator of IFNγ and IL-4 signalling, and that SOCS3 regulates cytokine-driven STAT3 phosphorylation following LPS stimulation. Interestingly, compound deletion of SOCS1 and SOCS3 synergistically up-regulated both inducible nitric oxide synthase (iNOS) and arginase I (ArgI) in response to LPS, and ArgI in response to IL-4 stimulation.  In conclusion, we find no evidence for redundancy between SOCS1 and SOCS3 as each regulate specific cytokine signalling cascades, however those signals converge on iNOS and ArgI. These two enzymes compete for a common substrate to regulate production of nitric oxide, and thus SOCS1 and SOCS3 coordinate regulation of the iNOS/ArgI axis and an important anti-pathogen effector mechanism.