Inhibition of Macrophage Complement Receptor CRIg by TRIM72 Polarizes Innate Immunity of the Lung

Am J Respir Cell Mol Biol. 2018 Jun;58(6):756-766. doi: 10.1165/rcmb.2017-0236OC.

Abstract

The complement system plays a critical role in immune responses against pathogens. However, its identity and regulation in the lung are not fully understood. This study aimed to explore the role of tripartite motif protein (TRIM) 72 in regulating complement receptor (CR) of the Ig superfamily (CRIg) in alveolar macrophage (AM) and innate immunity of the lung. Imaging, absorbance quantification, and flow cytometry were used to evaluate in vitro and in vivo AM phagocytosis with normal, or altered, TRIM72 expression. Pulldown, coimmunoprecipitation, and gradient binding assays were applied to examine TRIM72 and CRIg interaction. A pneumonia model was established by intratracheal injection of Pseudomonas aeruginosa. Mortality, lung bacterial burden, and cytokine levels in BAL fluid and lung tissues were examined. Our data show that TRIM72 inhibited CR-mediated phagocytosis, and release of TRIM72 inhibition led to increased AM phagocytosis. Biochemical assays identified CRIg as a binding partner of TRIM72, and TRIM72 inhibited formation of the CRIg-phagosome. Genetic ablation of TRIM72 led to improved pathogen clearance, reduced cytokine storm, and improved survival in murine models of severe pneumonia, specificity of which was confirmed by adoptive transfer of wild-type or TRIM72KO AMs to AM-depleted TRIM72KO mice. TRIM72 overexpression promoted bacteria-induced NF-κB activation in murine alveolar macrophage cells. Our data revealed a quiescent, noninflammatory bacterial clearance mechanism in the lung via AM CRIg, which is suppressed by TRIM72. In vivo data suggest that targeted suppression of TRIM72 in AM may be an effective measure to treat fatal pulmonary bacterial infections.

Keywords: NF-κB signaling; bacterial pneumonia; complement receptor of the Ig family; phagocytosis; tripartite motif-containing protein 72.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Immunity, Innate / physiology*
  • Lung / immunology*
  • Macrophages, Alveolar / immunology*
  • Membrane Proteins
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Phagocytosis / physiology
  • Phagosomes / metabolism
  • Pneumonia, Bacterial / metabolism
  • Pneumonia, Bacterial / pathology
  • Receptors, Complement 3b / metabolism*
  • Tripartite Motif Proteins

Substances

  • CR1 protein, human
  • Carrier Proteins
  • MG53 protein, mouse
  • Membrane Proteins
  • NF-kappa B
  • Receptors, Complement 3b
  • TRIM72 protein, human
  • Tripartite Motif Proteins