Article
ACKR2 contributes to pulmonary dysfunction by shaping CCL5:CCR5- dependent recruitment of lymphocytes during influenza A infection in mice
Registro en:
TAVARES, Luciana P. et al. ACKR2 contributes to pulmonary dysfunction by shaping CCL5:CCR5- dependent recruitment of lymphocytes during influenza A infection in mice. American Journal of Physiology. Lung Cellular and Molecular Physiology, v. 318, p. 1655-1670, Jan. 2020.
1522-1504
10.1152/ajplung.00134.2019
Autor
Tavares, Luciana P.
Garcia, Cristiana C.
Gonçalves, Ana Paula F.
Kraemer, Lucas R.
Melo, Eliza M.
Oliveira, Fabrício M. S.
Freitas, Camila S.
Lopes, Gabriel A. O.
Reis, Diego C.
Cassali, Geovanni D.
Machado, Alexandre M.
Mantovani, Alberto
Locati, Massimo
Teixeira, Mauro M.
Russo, Remo C.
Resumen
ACKR2 contributes to pulmonary dysfunction by shaping CCL5:
CCR5-dependent recruitment of lymphocytes during influenza A
infection in mice. Am J Physiol Lung Cell Mol Physiol 318:
L655–L670, 2020. First published January 29, 2020; doi:10.1152/
ajplung.00134.2019.—Inflammation triggered by influenza A virus
(IAV) infection is important for viral clearance, induction of adaptive
responses, and return to lung homeostasis. However, an exaggerated
immune response, characterized by the overproduction of chemokines,
can lead to intense lung injury, contributing to mortality.
Chemokine scavenger receptors, such as ACKR2, control the levels of
CC chemokines influencing the immune responses. Among the
chemokine targets of ACKR2, CCL5 is important to recruit and
activate lymphocytes. We investigated the role of ACKR2 during IAV
infection in mice. Pulmonary ACKR2 expression was increased
acutely after IAV infection preceding the virus-induced lung dysfunction.
ACKR2-knockout (ACKR2 / ) mice were protected from IAV,
presenting decreased viral burden and lung dysfunction. Mechanistically,
the absence of ACKR2 resulted in augmented airway CCL5
levels, secreted by mononuclear and plasma cells in the lung parenchyma.
The higher chemokine gradient led to an augmented recruitment
of T and B lymphocytes, formation of inducible bronchusassociated
lymphoid tissue and production of IgA in the airways of
ACKR2 / mice post-IAV. CCL5 neutralization in ACKR2 / mice
prevented lymphocyte recruitment and increased bronchoalveolar lavage
fluid protein levels and pulmonary dysfunction. Finally,
CCR5 / mice presented increased disease severity during IAV
infection, displaying increased neutrophils, pulmonary injury and
dysfunction, and accentuated lethality. Collectively, our data showed
that ACKR2 dampens CCL5 levels and the consequent recruitment of
CCR5 T helper 1 (Th1), T regulatory cells (Tregs), and B lymphocytes
during IAV infection, decreasing pathogen control and promoting
lung dysfunction in wild type mice. Therefore, ACKR2 is detrimental and CCR5 is protective during IAV infection coordinating
innate and adaptive immune responses in mice. 2023