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NOS1 and SOC1 work as a switch of macrophage functional phenotypes
Author(s) -
Blajszczak Chuck,
He Chenxia,
Gantner Benjamin N,
Bonini Marcelo
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb502
Subject(s) - nos1 , inflammation , nitric oxide , suppressor of cytokine signaling 1 , cytokine , microbiology and biotechnology , tlr4 , tumor necrosis factor alpha , macrophage , phenotype , nitric oxide synthase , chemistry , immunology , biology , suppressor , biochemistry , in vitro , endocrinology , gene
Nitric oxide synthases are enzymes involved in the production of nitric oxide (NO) from L‐arginine. NO is an important molecule with critical roles in signaling including inflammatory signaling. We found that differently than other isoforms, NOS1 (neuronal NOS or nNOS) is unique in the sense it promotes inflammation. We have uncovered that NOS1 is actually essential to start and amplify inflammation. This is because we demonstrated that in contrast to the enhanced susceptibility of NOS2 −/− and NOS3 −/− mice to inflammatory stimuli (i.e. LPS), NOS1 −/− mice are, in fact, resistant both in terms of lethality and tissue injury. We also show that NOS1 deficiency not only attenuates TLR4‐stimulated pro‐inflammatory cytokine production but it also switches cytokine profiles from pro‐ to anti‐inflammation in macrophages. We found that this is because NOS1 inhibits SOCS1 which normally degrades p65 inhibiting the master regulator of inflammation NF‐κB (p65/p50 heterodimer). Hence, the suppression of NOS1 activates SOCS1 leading to the degradation of NFkB p65/p50 (inflammatory configuration) and the accumulation of p50/p50 (anti‐inflammatory configuration). Moreover we show here that the transplant of NOS1−/− macrophages which assume an anti‐inflammatory phenotype corrects exaggerated inflammation in vivo. Mechanisms will be discussed. Support or Funding Information NA