Escherichia coli-induced gut IL-33 release inhibits lung type 2 allergic responses

Keywords

● Allergic asthma

● Gut-lung axis

● IL-33-signaling

Main Findings

In this preprint, the authors investigate how enteric bacterial infections shape distal allergic immune responses through a gut-lung regulatory axis. Based on emerging evidence that epithelial alarmins and type 2 innate lymphoid cells (ILC2s) coordinate tissue-specific immunity, the authors examine whether infection with enterotoxigenic Escherichia coli (ETEC) alters lung type 2 allergic inflammation. Using an oral ETEC infection and purified heat-labile toxin (LT), the authors demonstrate that enteric epithelial damage induces IL-33 release in the gut, leading to a robust accumulation of gut eosinophils and ILC2s. Surprisingly, this gut-restricted IL-33 response following ETEC infection resulted in a marked suppression of allergic asthma in the lung following allergen and Papain or IL-33 challenge, resulting in the reduced activation and accumulation of lung eosinophils and ILC2s. To dissect this ETEC-induced protection via the gut-lung communication axis, the authors used a combination of a global and epithelial-specific (Villin-Cre) IL-33 deletion, and ILC2-deficient mice. Here, the authors demonstrate that both gut-derived IL-33 and ILC2s are required for this ETEC-induced protective effect against allergic asthma. Mechanistically, the authors show that LT exposure locally reprograms lung ILC2s (usually expressing high levels of the IL-33 receptor ST2) into an ST2-low, IL-33-hyporesponsive state without requiring the recruitment of ILC2 from other tissues. They demonstrate this through intranasal CFSE fate-mapping and proliferation assays. In summary, this preprint reveals a previously unrecognized gut-to-lung immune circuit in which enteric IL-33 driven eosinophil and ILC2 accumulation and activation in the gut remotely suppresses allergen-driven asthma in the lung. This work ultimately provides mechanistic insight into how microbial infection can protect against allergic disease.

Limitations

· While this study convincingly establishes that ETEC/LT infection drives IL-33 release in the gut and operates via ILC2s to elicit suppressive effects in the lung, the molecular signal/s that communicate/s between the gut and the lung was not identified. It remains unclear how communication between the gut and lung are established and sustained. This becomes important when hypothesizing that the observed response is specific to ETEC/LT infection. A different hypothesis may propose that the reported adaptations across gut and lung are a universal response to gut epithelial stress. Dissecting this and identifying putative mediator(s) responsible for the effects reported by the authors would help to determine whether infection or epithelial disruption are the underlying mode mediating the reported protective benefits.

· The authors do a wonderful job of identifying changes in eosinophil and ILC2 numbers and activation status in the gut and lung following ETEC/LT infection and allergic asthma, but fall short on characterizing the remaining elements of the immune system. What are the effects on other cells that contribute to allergic inflammation? Does ETEC/LT impact T cell and B cell subsets in the lung and gut and does the infection impact the production of allergen-specific IgE and the sensitization response? Would infection impact the numbers and/or phenotype of lung-resident mast cells that drive inflammatory reactions?

· An induction in IL-33 hyporesponsivness within ILC2 implies immune regulation by ETEC/LT. Would other ILC2-controlled responses can be impacted by ETEC/LT? Is ETEC/LT infection only protective during type 2 inflammation or could other pathologies like flu bacterial pneumonia be affected too?

Significance/Novelty

The authors identified a previously unrecognized and unconventional gut-lung immunoregulatory network in which enteric bacterial infection reprograms lung type 2 immunity. They convincingly demonstrate that gut epithelial IL-33 release and local ILC2 activation drive a distal suppression of lung eosinophils and ILC2s, revealing that tissue-resident ILC2s and type 2 immune responses in the lung can be regulated by immune events occurring in distant organs.

 

This work provides important insight into how immune responses are coordinated across tissue barriers, demonstrating that enteric infections can remotely regulate lung immune responses. Additionally, these findings offer a mechanistic framework for how microbial exposure may be protective against allergic asthma, highlighting the potential for immune reprogramming strategies that dampen pathological inflammation without broadly supressing immunity.

Credit

Reviewed by Robert Crozier (University of Toronto, Department of Immunology) as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.