SEMA3E REGULATES RESIDENT MACROPHAGES RESPONSE IN LIPOPOLYSACCHARIDE-INDUCED SEPSIS
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Date
2016
Authors
Mohammed, Ashfaque
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Abstract
Sepsis is an overwhelming systemic inflammatory response to microbial infections.
Macrophages are the key innate immune cells that provide the first line of defence against
systemic infections during sepsis. Macrophages perform multiple functions during
infections such as triggering inflammation, phagocytosis of microbes, and resolution of
inflammation. So far, various molecules have been shown to be involved in the regulation
of macrophages in inflammatory conditions. However, recently published studies suggest
that Semaphorin3E (Sema3E) plays a pivotal role in the immune function of
macrophages. The exact role of Sema3E associated with macrophages function in
lipopolysaccharide (LPS) induced endotoxemia is unknown. To directly address the
involvement of Sema3E in macrophages, we have used Sema3e gene deletion approaches
in in vivo and cell-based setups. We found that Sema3e-/- mice displayed initial transient
protection from LPS-induced hypothermia. Sema3e-/- mice showed lower inducible nitric
oxide synthase (iNOS) expression in peritoneal macrophages without altering the
integrity of TLR-4 after LPS injection. Sema3e-/- mice exhibit a lower level of tumour
necrosis factor (TNF) and interleukin-6 (IL-6) in peritoneal lavage and serum as
compared to wild type (WT) littermates. Bone marrow derived macrophages (BMDMs)
from Sema3e-/- mice expressed low levels of pro-inflammatory cytokines and also
exhibited significantly down-regulated phosphorylation of STAT3, ERK1/2, and NF-κB,
upon LPS exposure. Overall, the current study provides direct evidence that the lack of
Sema3E, makes macrophages to become less responsive to LPS by disturbing LPSIII
initiated signaling transduction. These findings suggest that the inhibition of Sema3E
might be a novel strategy to treat conditions triggered by the excessive production of
inflammatory cytokines.
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Keywords
Sema3E, Sepsis, Macrophages