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Pla2g5 contributes to viral-induced lung inflammation through macrophage proliferation and LA/Ffar1 lung cell recruitment
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  • Barbara Balestrieri,
  • Masaya Koganesawa,
  • Daniel Dwyer,
  • Kinan Alhallak,
  • Jun Nagai,
  • Sachin Samuchiwal,
  • Hayashi Hiroaki,
  • Airi Nishida,
  • Thomas Hirsch,
  • Patrick J. Brennan,
  • Mark Puder
Barbara Balestrieri
Mass General Brigham Inc

Corresponding Author:[email protected]

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Masaya Koganesawa
Mass General Brigham Inc
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Daniel Dwyer
Mass General Brigham Inc
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Kinan Alhallak
Mass General Brigham Inc
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Jun Nagai
Mass General Brigham Inc
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Sachin Samuchiwal
Mass General Brigham Inc
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Hayashi Hiroaki
Mass General Brigham Inc
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Airi Nishida
Mass General Brigham Inc
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Thomas Hirsch
Boston Children's Hospital
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Patrick J. Brennan
Mass General Brigham Inc
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Mark Puder
Boston Children's Hospital
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Abstract

Macrophages expressing group V phospholipase A 2 (Pla2g5) release the Free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5flox/flox mice, deleted Pla2g5 by using the Cx3Cr1cre transgene, and activated bone marrow-derived macrophages (BM-Macs) with Poly:IC, a synthetic double-stranded RNA that triggers a viral-like immune response, Poly:IC+LA, and known Pla2g5-dependent stimuli (IL-4, LPS+IFNg and IL-33+IL-4+GM-CSF) followed by lipidomic and transcriptomic analysis. In absence of Pla2g5, PolyI: IC-activated BM-Macs had a reduction of major bioactive lipids and critical enzymes producing those bioactive lipids. Additionally, AKT phosphorylation was reduced in Poly:IC stimulated BM-Macs lacking Pla2g5, which was not restored by adding LA to Poly:IC. Furthermore, Pla2g5flox/flox; Cx3cr1cre/+ mice had diminished Poly:IC-induced lung inflammation, including inflammatory macrophage proliferation; adding LA to Poly:IC partially restored lung inflammation. Additionally, mice lacking FFA receptor-1, ( Ffar1)-null mice had reduced Poly: IC-induced lung cell recruitment, not corrected by LA. Thus, Pla2g5 contributes to Poly: IC-induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1 lung cell recruitment.