ATG16L1 in myeloid cells limits colorectal tumor growth in Apc Min/+ mice infected with colibactin-producing Escherichia coli via decreasing inflammasome activation
Résumé
Escherichia coli strains producing the genotoxin colibactin, designated as CoPEC (colibactin-producing E. coli), have emerged as an important player in the etiology of colorectal cancer (CRC). Here, we investigated the role of macroautophagy/autophagy in myeloid cells, an important component of the tumor microenvironment, in the tumorigenesis of a susceptible mouse model infected with CoPEC. For that, a preclinical mouse model of CRC, the Apc(Min/+) mice, with Atg16l1 deficiency specifically in myeloid cells (Apc(Min/+)/Atg16l1[triangle MC]) and the corresponding control mice (Apc(Min/+)), were infected with a clinical CoPEC strain 11G5 or its isogenic mutant 11G5 triangle clbQ that does not produce colibactin. We showed that myeloid cell-specific Atg16l1 deficiency led to an increase in the volume of colonic tumors in Apc(Min/+) mice under infection with 11G5, but not with 11G5 triangle clbQ. This was accompanied by increased colonocyte proliferation, enhanced inflammasome activation and IL1B/IL-1 beta secretion, increased neutrophil number and decreased total T cell and cytotoxic CD8(+) T cell numbers in the colonic mucosa and tumors. In bone marrow-derived macrophages (BMDMs), compared to uninfected and 11G5 triangle clbQ-infected conditions, 11G5 infection increased inflammasome activation and IL1B secretion, and this was further enhanced by autophagy deficiency. These data indicate that ATG16L1 in myeloid cells was necessary to inhibit colonic tumor growth in CoPEC-infected Apc(Min/+) mice via inhibiting colibactin-induced inflammasome activation and modulating immune cell response in the tumor microenvironment. Abbreviation: AOM, azoxymethane; APC, APC regulator of WNT signaling pathway; ATG, autophagy related; Atg16l1[triangle MC] mice, mice deficient for Atg16l1 specifically in myeloid cells; CASP1, caspase 1; BMDM, bone marrow-derived macrophage; CFU, colony-forming unit; CoPEC, colibactin-producing Escherichia coli; CRC, colorectal cancer; CXCL1/KC, C-X-C motif chemokine ligand 1; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; MC, myeloid cell; MOI, multiplicity of infection; PBS, phosphate-buffered saline; pks, polyketide synthase; qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; siRNA, small interfering RNA; TME, tumor microenvironment; TNF/TNF-alpha, tumor necrosis factor.
Mots clés
AOM
azoxymethane APC
APC regulator of WNT signaling pathway ATG
autophagy related Atg16l1[∆MC] mice
mice deficient for Atg16l1 specifically in myeloid cells CASP1
caspase 1 BMDM
bone marrow-derived macrophage CFU
colony-forming unit CoPEC
colibactin-producing Escherichia coli CRC
colorectal cancer CXCL1/KC
C-X-C motif chemokine ligand 1 ELISA
enzyme-linked immunosorbent assay IL
interleukin MC
myeloid cell MOI
multiplicity of infection PBS
phosphatebuffered saline pks
polyketide synthase qRT-PCR
quantitative real-time reverse-transcription polymerase chain reaction siRNA
small interfering RNA TME
tumor microenvironment TNF/TNF-α
tumor necrosis factor Autophagy bacterial infection colibactinproducing E. coli colorectal cancer toxin
azoxymethane
APC
APC regulator of WNT signaling pathway
ATG
autophagy related
Atg16l1[∆MC] mice
mice deficient for Atg16l1 specifically in myeloid cells
CASP1
caspase 1
BMDM
bone marrow-derived macrophage
CFU
colony-forming unit
CoPEC
colibactin-producing Escherichia coli
CRC
colorectal cancer
CXCL1/KC
C-X-C motif chemokine ligand 1
ELISA
enzyme-linked immunosorbent assay
IL
interleukin
MC
myeloid cell
MOI
multiplicity of infection
PBS
phosphatebuffered saline
pks
polyketide synthase
qRT-PCR
quantitative real-time reverse-transcription polymerase chain reaction
siRNA
small interfering RNA
TME
tumor microenvironment
TNF/TNF-α
tumor necrosis factor Autophagy
bacterial infection
colibactinproducing E. coli
toxin
Domaines
Sciences du Vivant [q-bio]
Fichier principal
ATG16L1 in myeloid cells limits colorectal tumor growth in ApcMin mice infected with colibactin-producing Escherichia coli via decreasing inflammaso.pdf (8.89 Mo)
Télécharger le fichier
| Origine | Publication financée par une institution |
|---|