ATG16L1 in myeloid cells limits colorectal tumor growth in Apc ^Min/+ mice infected with colibactin-producing Escherichia coli via decreasing inflammasome activation

Laurène Salesse (1) , Angéline Duval (1) , Pierre Sauvanet (1) , Alison da Silva (1) , Nicolas Barnich (1) , Catherine Godfraind (1) , Guillaume Dalmasso (1) , Hang Thi Thu Nguyen (1)

1 M2iSH - Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte

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]

Laurène Salesse, Angéline Duval, Pierre Sauvanet, Alison da Silva, Nicolas Barnich, et al.. ATG16L1 in myeloid cells limits colorectal tumor growth in Apc ^Min/+ mice infected with colibactin-producing Escherichia coli via decreasing inflammasome activation. Autophagy, 2024, pp.1 - 19. ⟨10.1080/15548627.2024.2359770⟩. ⟨hal-04654209⟩