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Cell Rep. 2019 May 14;27(7):2119-2131.e6. doi: 10.1016/j.celrep.2019.04.072.

VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection.

Author information

1
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada.
2
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
4
Department of Anesthesiology, Irving Medical Center, Columbia University, New York, NY 10032, USA.
5
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada.
6
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
7
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada; Department of Obstetrics and Gynecology, and Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
8
Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: msandor@wisc.edu.

Abstract

Many autoimmune and infectious diseases are characterized by the formation of granulomas which are inflammatory lesions that consist of spatially organized immune cells. These sites protect the host and control pathogens like Mycobacterium tuberculosis (Mtb), but are highly inflammatory and cause pathology. Using bacille Calmette-Guerin (BCG) and Mtb infection in mice that induce sarcoid or caseating granulomas, we show that a subpopulation of granuloma macrophages produces vascular endothelial growth factor (VEGF-A), which recruits immune cells to the granuloma by a non-angiogenic pathway. Selective blockade of VEGF-A in myeloid cells, combined with granuloma transplantation, shows that granuloma VEGF-A regulates granulomatous inflammation. The severity of granuloma-related inflammation can be ameliorated by pharmaceutical or genetic inhibition of VEGF-A, which improves survival of mice infected with virulent Mtb without altering host protection. These data show that VEGF-A inhibitors could be used as a host-directed therapy against granulomatous diseases like tuberculosis and sarcoidosis, thereby expanding the value of already existing and approved anti-VEGF-A drugs.

KEYWORDS:

P2RX7; VEGF-A; granuloma; inflammation; monocyte recruitment; mycobacterium; sarcoidosis; tuberculosis

PMID:
31091450
DOI:
10.1016/j.celrep.2019.04.072
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