Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota

Abstract

As a conserved pathway that lies at the intersection between host defence and cellular homeostasis, autophagy serves as a rheostat for immune reactions. In particular, autophagy suppresses excess type I interferon (IFN-I) production in response to viral nucleic acids. It is unknown how this function of autophagy relates to the intestinal barrier where host-microbe interactions are pervasive and perpetual. Here, we demonstrate that mice deficient in autophagy proteins are protected from the intestinal bacterial pathogen Citrobacter rodentium in a manner dependent on IFN-I signalling and nucleic acid sensing pathways. Enhanced IFN-stimulated gene expression in intestinal tissue of autophagy-deficient mice in the absence of infection was mediated by the gut microbiota. Additionally, monocytes infiltrating into the autophagy-deficient intestinal microenvironment displayed an enhanced inflammatory profile and were necessary for protection against C. rodentium. Finally, we demonstrate that the microbiota-dependent IFN-I production that occurs in the autophagy-deficient host also protects against chemical injury of the intestine. Thus, autophagy proteins prevent a spontaneous IFN-I response to microbiota that is beneficial in the presence of infectious and non-infectious intestinal hazards. These results identify a role for autophagy proteins in controlling the magnitude of IFN-I signalling at the intestinal barrier.

Mycobacterium tuberculosis, antimicrobials, immunity, and lung–gut microbiota crosstalk: current updates and emerging advances

“…Moreover, cytoplasmic lysozyme levels were reduced and protective molecules, such as MUC2, were highly expressed by goblet cells, an indication of the altered inner intestinal layer resulting from overactivated immune response in the absence of ATG. 38,46 From previous studies, the absence of autophagy increased the inflammatory response, essentially altering the microbiome and intestinal layer; 40,48 however, this is yet to be demonstrated in the airway microbiota-Mtb interaction.…”

“…In the case of C. rodentium, autophagycompetent monocytes attracted to the infection site aided in the resolution of the infection. 48 In effect, autophagy influences the composition of the intestinal microbiota through IFN-I inhibition.…”

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

“…However, other studies have reported that autophagy deficiency increases resistance to infection with C. rodentium [80,81]. Marchiando et al reported that compared to WT mice, Atg16l1[HM] mice are more resistant to C. rodentium infection, displayed by reduced number of C. rodentium associated to the colon and caecum, increased survival, decreased weight loss and diarrheal disease and protection from colonic inflammation [80].…”

Genome-wide association study of Buruli ulcer in rural Benin highlights role of two LncRNAs and the autophagy pathway

“…In addition, Atg16L1-hypomorphic mice developed intestinal abnormalities resembling CD whilst displaying resistance to intestinal infection with the bacterium Citrobacter rodentium 45,46 . Published findings suggest that autophagy may serve as a rheostat for immune reactions 47 . These opposite effects in Buruli ulcer and CD provide another example of mirror genetic effects (i.e.…”