TY - JOUR
T1 - The GPCR adaptor protein norbin suppresses the neutrophil-mediated immunity of mice to pneumococcal infection
AU - Pantarelli, Chiara
AU - Pan, Dingxin
AU - Chetwynd, Stephen
AU - Stark, Anne-Katrien
AU - Hornigold, Kirsti
AU - Machin, Polly
AU - Crossland, Laraine
AU - Cleary, Simon J.
AU - Baker, Martin J.
AU - Hampson, Elizabeth
AU - Mandel, Anna
AU - Segonds-Pichon, Anne
AU - Walker, Rachael
AU - van t Veer, Cornelis
AU - Riffo-Vasquez, Yanira
AU - Okkenhaug, Klaus
AU - Pitchford, Simon
AU - Welch, Heidi C. E.
N1 - Publisher Copyright: © 2021 American Society of Hematology. All rights reserved.
PY - 2021/8/24
Y1 - 2021/8/24
N2 - 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 neutrophilmediated 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.
AB - 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 neutrophilmediated 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.
UR - http://www.scopus.com/inward/record.url?scp=85113869145&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/bloodadvances.2020002782
DO - https://doi.org/10.1182/bloodadvances.2020002782
M3 - Article
C2 - 34402884
SN - 2473-9529
VL - 5
SP - 3076
EP - 3091
JO - Blood advances
JF - Blood advances
IS - 16
ER -