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L-selectin shedding affects bacterial clearance in the lung - a new regulatory pathway for integrin-outside-in signaling

Anika Cappenberg, Andreas Margraf, Katharina Thomas, Bernadette Bardel, Dylan A. McCreedy, Veerle Van Marck, Alexander Mellmann, Clifford A. Lowell and Alexander Zarbock

Key Points

  • L-selectin amplifies integrin outside-in-signaling and is needed for host defense and bacterial clearance in K.pneumoniae induced pneumonia

  • IRhom2 dependent ADAM17 activation leads to L-selectin shedding and subsequently amplifies neutrophil effector functions

Abstract

Pneumonia induced by gram-negative bacteria is a common and serious disease associated with high morbidity and mortality. Elimination of bacterial pathogens relies on the recruitment and functions of neutrophils. The adhesion molecule L-selectin has recently been implicated in integrin activation in neutrophils (inside-out-signaling). However, the molecular mechanism how L-selectin participates in host defense against Klebsiella pneumoniae-induced pulmonary inflammation is unknown. We demonstrate that L-selectin-deficient-mice are prone to pulmonary infection compared to WT controls. Mechanistically, L-selectin cleavage from the neutrophil surface triggered by integrin engagement is involved in neutrophil recruitment into the lung and bacterial clearance. Downstream of integrin-ligation, the metalloproteinase ADAM17 sheds L-selectin from the neutrophil surface in an IRhom2-dependent manner. L-selectin cleavage enhances integrin-mediated outside-in signaling resulting in increased neutrophil effector functions. Thus, we identify a novel regulatory mechanism in neutrophils required for an adequate immune response triggered by integrin engagement during Klebsiella pneumoniae-induced pulmonary Inflammation.

  • Submitted March 20, 2019.
  • Revision received July 31, 2019.
  • Accepted July 24, 2019.