The GPCR adaptor protein norbin suppresses the neutrophil-mediated immunity of mice to pneumococcal infection.

Abstract

Streptococcal pneumonia is a worldwide health problem that kills ∼2 million people each year, particularly young children, the elderly, and immunosuppressed individuals. Alveolar macrophages and neutrophils provide the early innate immune response to clear pneumococcus from infected lungs. However, the level of neutrophil involvement is context dependent, both in humans and in mouse models of the disease, influenced by factors such as bacterial load, age, and coinfections. Here, we show that the G protein-coupled receptor (GPCR) adaptor protein norbin (neurochondrin, NCDN), which was hitherto known as a regulator of neuronal function, is a suppressor of neutrophil-mediated innate immunity. Myeloid norbin deficiency improved the immunity of mice to pneumococcal infection by increasing the involvement of neutrophils in clearing the bacteria, without affecting neutrophil recruitment or causing autoinflammation. It also improved immunity during Escherichia coli-induced septic peritonitis. It increased the responsiveness of neutrophils to a range of stimuli, promoting their ability to kill bacteria in a reactive oxygen species-dependent manner, enhancing degranulation, phagocytosis, and the production of reactive oxygen species and neutrophil extracellular traps, raising the cell surface levels of selected GPCRs, and increasing GPCR-dependent Rac and Erk signaling. The Rac guanine-nucleotide exchange factor Prex1, a known effector of norbin, was dispensable for most of these effects, which suggested that norbin controls additional downstream targets. We identified the Rac guanine-nucleotide exchange factor Vav as one of these effectors. In summary, our study presents the GPCR adaptor protein norbin as an immune suppressor that limits the ability of neutrophils to clear bacterial infections.

• Authors: Chiara Pantarelli, Dingxin Pan, Stephen Chetwynd, Anne-Katrien Stark, Kirsti Hornigold, Polly Machin, Laraine Crossland, Simon J Cleary, Martin J Baker, Elizabeth Hampson, Anna Mandel, Anne Segonds-Pichon, Rachael Walker, Cornelis van 't Veer, Yanira Riffo-Vasquez, Klaus Okkenhaug, Simon Pitchford, Heidi C E Welch
• Journal: Blood advances (Blood Adv) Vol. 5 Issue 16 Pg. 3076-3091 (08 24 2021) ISSN: 2473-9537 [Electronic] United States
• PMID: 34402884 (Publication Type: Journal Article)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Neuropeptides
• Receptors, G-Protein-Coupled
• norbin

Topics

• Animals
• Mice
• Mice, Knockout
• Neuropeptides
• Neutrophils
• Pneumococcal Infections
• Receptors, G-Protein-Coupled