TY - JOUR
T1 - Helicobacter pylori Dampens HLA-II Expression on Macrophages via the Up-Regulation of miRNAs Targeting CIITA
AU - Codolo, Gaia
AU - Toffoletto, Marta
AU - Chemello, Francesco
AU - Coletta, Sara
AU - Soler Teixidor, Gemma
AU - Battaggia, Greta
AU - Munari, Giada
AU - Fassan, Matteo
AU - Cagnin, Stefano
AU - de Bernard, Marina
N1 - Funding Information:
We acknowledge Bando Grandi Attrezzature 2015 University of Padova (Italy) (Prot. 5086) for the acquirement of digital and qPCR systems (BioRad). Funding. We thank the Integrated Department Budget from the University of Padova (CPDA 139317 to SCa and BIRD 183429/18 to GC); the CARIPLO Foundation (2016?1006 to SCa and GL); the Italian Ministry of Health (GR-2011?02346845 to SCa); AIRC (IG 2015 Id.17773 to SCa); and Agenzia Nazionale di Valutazione del Sistema Universitario e della Ricerca (ANVUR) (FFABR- 2017 to SCa) for support.
PY - 2020/1/8
Y1 - 2020/1/8
N2 - Macrophages have a major role in infectious and inflammatory diseases, and the available data suggest that Helicobacter pylori persistence can be explained in part by the failure of the bacterium to be killed by professional phagocytes. Macrophages are cells ready to kill the engulfed pathogen, through oxygen-dependent and -independent mechanisms; however, their killing potential can be further augmented by the intervention of T helper (Th) cells upon the specific recognition of human leukocyte antigen (HLA)-II–peptide complexes on the surface of the phagocytic cells. As it pertains to H. pylori, the bacterium is engulfed by macrophages, but it interferes with the phagosome maturation process leading to phagosomes with an altered degradative capacity, and to megasomes, wherein H. pylori resists killing. We recently showed that macrophages infected with H. pylori strongly reduce the expression of HLA-II molecules on the plasma membrane and this compromises the bacterial antigen presentation to Th lymphocytes. In this work, we demonstrate that H. pylori hampers HLA-II expression in macrophages, activated or non-activated by IFN-γ, by down-regulating the expression of the class II major histocompatibility complex transactivator (CIITA), the “master control factor” for the expression of HLA class II genes. We provided evidence that this effect relies on the up-regulation of let-7f-5p, let-7i-5p, miR-146b-5p, and -185-5p targeting CIITA. MiRNA expression analysis performed on biopsies from H. pylori-infected patients confirmed the up-regulation of let-7i-5p, miR-146b-5p, and -185-5p in gastritis, in pre-invasive lesions, and in gastric cancer. Taken together, our results suggest that specific miRNAs may be directly involved in the H. pylori infection persistence and may contribute to confer the risk of developing gastric neoplasia in infected patients.
AB - Macrophages have a major role in infectious and inflammatory diseases, and the available data suggest that Helicobacter pylori persistence can be explained in part by the failure of the bacterium to be killed by professional phagocytes. Macrophages are cells ready to kill the engulfed pathogen, through oxygen-dependent and -independent mechanisms; however, their killing potential can be further augmented by the intervention of T helper (Th) cells upon the specific recognition of human leukocyte antigen (HLA)-II–peptide complexes on the surface of the phagocytic cells. As it pertains to H. pylori, the bacterium is engulfed by macrophages, but it interferes with the phagosome maturation process leading to phagosomes with an altered degradative capacity, and to megasomes, wherein H. pylori resists killing. We recently showed that macrophages infected with H. pylori strongly reduce the expression of HLA-II molecules on the plasma membrane and this compromises the bacterial antigen presentation to Th lymphocytes. In this work, we demonstrate that H. pylori hampers HLA-II expression in macrophages, activated or non-activated by IFN-γ, by down-regulating the expression of the class II major histocompatibility complex transactivator (CIITA), the “master control factor” for the expression of HLA class II genes. We provided evidence that this effect relies on the up-regulation of let-7f-5p, let-7i-5p, miR-146b-5p, and -185-5p targeting CIITA. MiRNA expression analysis performed on biopsies from H. pylori-infected patients confirmed the up-regulation of let-7i-5p, miR-146b-5p, and -185-5p in gastritis, in pre-invasive lesions, and in gastric cancer. Taken together, our results suggest that specific miRNAs may be directly involved in the H. pylori infection persistence and may contribute to confer the risk of developing gastric neoplasia in infected patients.
KW - antigen presentation
KW - gastric cancer
KW - Helicobacter pylori
KW - macrophages
KW - miRNA
UR - http://www.scopus.com/inward/record.url?scp=85078268049&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078268049&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2019.02923
DO - 10.3389/fimmu.2019.02923
M3 - Article
C2 - 31969878
AN - SCOPUS:85078268049
VL - 10
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 2923
ER -