Ecto-5′-Nucleotidase (CD73) Deficiency in Mycobacterium tuberculosis-Infected Mice Enhances Neutrophil Recruitment

Abstract

The immune system needs safeguards that prevent collateral tissue damage mediated by the immune system while enabling an effective response against a pathogen. The purinergic pathway is one such mechanism and finely modulates inflammation by sensing nucleotides in the environment. Extracellular ATP is considered to be a danger signal leading to a proinflammatory response, whereas adenosine is immunosuppressive. CD73, also called ecto-5=-nucleotidase, occupies a strategic position in this pathway, as it is the main enzyme responsible for the generation of adenosine from ATP. Here, we explore the role of CD73 during tuberculosis, a disease characterized by an immune response that is harmful to the host and unable to eradicate Mycobacterium tuberculosis. Using CD73 knockout (KO) mice, we found that CD73 regulates the response to M. tuberculosis infection in vitro and in vivo. Mycobacterium-infected murine macrophages derived from CD73 KO mice secrete more keratinocyte chemoattractant (KC), tumor necrosis factor alpha (TNF-␣), and interleukin-6 (IL-6) and release less vascular endothelial growth factor (VEGF) upon ATP stimulation than do those derived from wild-type (WT) mice. In vivo, CD73 limits the early influx of neutrophils to the lungs without affecting bacterial growth and dissemination. Collectively, our results support the view that CD73 fine-tunes antimycobacterial immune responses.

Innate immunity in tuberculosis: host defense vs pathogen evasion

“…53 Another study found that CD73 (also called ecto-5′-nucleotidase) limits the early influx of neutrophils into the lungs without affecting bacterial growth and dissemination, supporting the view that CD73 fine-tunes anti-mycobacterial immune responses. 54 Neutrophils can also be actively manipulated by Mtb. For example, Mtb induces neutrophil necrosis and prevents apoptosis dependent on region of difference 1 (RD-1)-encoded virulence factors.…”

Purinergic Signaling: A Common Path in the Macrophage Response against Mycobacterium tuberculosis and Toxoplasma gondii

“…This was also supported by the downregulation of CD73 expression in the small intestine during lethal ileitis triggered by oral infection of C57BL/6 mice, leading to an impaired capacity to produce eADO (Francois et al, 2015 ). By contrast, CD73 was not involved in the protection of M. tuberculosis -infected mice either at early stage of the infection or after 2 months of infection (Petit-Jentreau et al, 2015 ). Although M. tuberculosis -infected mice lacking the receptor were not more susceptible to TB than their WT counterpart, they presented a higher inflammation in the lungs due to the absence of eADO (Petit-Jentreau et al, 2015 ).…”

“…By contrast, CD73 was not involved in the protection of M. tuberculosis -infected mice either at early stage of the infection or after 2 months of infection (Petit-Jentreau et al, 2015 ). Although M. tuberculosis -infected mice lacking the receptor were not more susceptible to TB than their WT counterpart, they presented a higher inflammation in the lungs due to the absence of eADO (Petit-Jentreau et al, 2015 ). The lungs of M. tuberculosis -infected CD73 KO showed a higher neutrophil recruitment at early stage of the infection compared to WT mice (Petit-Jentreau et al, 2015 ).…”

“…Although M. tuberculosis -infected mice lacking the receptor were not more susceptible to TB than their WT counterpart, they presented a higher inflammation in the lungs due to the absence of eADO (Petit-Jentreau et al, 2015 ). The lungs of M. tuberculosis -infected CD73 KO showed a higher neutrophil recruitment at early stage of the infection compared to WT mice (Petit-Jentreau et al, 2015 ). The ectonucleotidase CD73 can also prevent the early recruitment of neutrophils on the site of the infection after T. gondii invasion limiting the inflammation (Mahamed et al, 2015 ).…”

Ecto-5' -Nucleotidase CD73 (NT5E), vitamin D receptor and FGF23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients – Data from the German Calciphylaxis Registry

“…CD73 plays a role of fine-tuning the effects within the purinergic signalling pathway. Adenosine, which is mainly produced by CD73 locally, attenuates both the pro-inflammatory [ 23 ] and the pain-stimulatory response[ 24 ] initiated by eATP. CD73 knock-out mice seem to cope better than patients with inactivating CD73 mutations as far as calcification is concerned.…”