TY - JOUR
T1 - Antifibrotics modify B-cell-induced fibroblast migration and activation in patients with idiopathic pulmonary fibrosis
AU - Ali, Mohamed F.
AU - Egan, Ashley M.
AU - Shaughnessy, Gaja F.
AU - Anderson, Dagny K.
AU - Kottom, Theodore J.
AU - Dasari, Harika
AU - Van Keulen, Virginia P.
AU - Aubry, Marie Christine
AU - Yi, Eunhee S.
AU - Limper, Andrew H.
AU - Peikert, Tobias
AU - Carmona, Eva M.
N1 - Funding Information:
Supported by the U.S. National Institutes of Health (grants K08HL112849 and R03HL144427) and by funds from the Annenberg to E.M.C. and the Hurvis Foundation to E.M.C.
Publisher Copyright:
Copyright © 2021 by the American Thoracic Society.
PY - 2021/6
Y1 - 2021/6
N2 - B-cell activation is increasingly linked to numerous fibrotic lung diseases, and it is well known that aggregates of lymphocytes form in the lung of many of these patients. Activation of B-cells by pattern recognition receptors (PRRs) drives the release of inflammatory cytokines, chemokines, and metalloproteases important in the pathophysiology of pulmonary fibrosis. However, the specific mechanisms of B-cell activation in patients with idiopathic pulmonary fibrosis (IPF) are poorly understood. Herein, we have demonstrated that B-cell activation by microbial antigens contributes to the inflammatory and profibrotic milieu seen in patients with IPF. B-cell stimulation by CpG and β-glucan via PRRs resulted in activation of mTOR-dependent and independent pathways. Moreover, we showed that the B-cell-secreted inflammatory milieu is specific to the inducing antigen and causes differential fibroblast migration and activation. B-cell responses to infectious agents and subsequent B-cell-mediated fibroblast activation are modifiable by antifibrotics, but each seems to exert a specific and different effect. These results suggest that, upon PRR activation by microbial antigens, B-cells can contribute to the inflammatory and fibrotic changes seen in patients with IPF, and antifibrotics are able to at least partially reverse these responses.
AB - B-cell activation is increasingly linked to numerous fibrotic lung diseases, and it is well known that aggregates of lymphocytes form in the lung of many of these patients. Activation of B-cells by pattern recognition receptors (PRRs) drives the release of inflammatory cytokines, chemokines, and metalloproteases important in the pathophysiology of pulmonary fibrosis. However, the specific mechanisms of B-cell activation in patients with idiopathic pulmonary fibrosis (IPF) are poorly understood. Herein, we have demonstrated that B-cell activation by microbial antigens contributes to the inflammatory and profibrotic milieu seen in patients with IPF. B-cell stimulation by CpG and β-glucan via PRRs resulted in activation of mTOR-dependent and independent pathways. Moreover, we showed that the B-cell-secreted inflammatory milieu is specific to the inducing antigen and causes differential fibroblast migration and activation. B-cell responses to infectious agents and subsequent B-cell-mediated fibroblast activation are modifiable by antifibrotics, but each seems to exert a specific and different effect. These results suggest that, upon PRR activation by microbial antigens, B-cells can contribute to the inflammatory and fibrotic changes seen in patients with IPF, and antifibrotics are able to at least partially reverse these responses.
KW - Antifibrotics
KW - B-lymphocytes
KW - Fibrosis
KW - Idiopathic pulmonary fibrosis
KW - Pattern recognition receptor
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U2 - 10.1165/rcmb.2020-0387OC
DO - 10.1165/rcmb.2020-0387OC
M3 - Article
C2 - 33689587
AN - SCOPUS:85107903166
SN - 1044-1549
VL - 64
SP - 722
EP - 733
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 6
ER -