Interleukin-33/IL-1RL1 axis modulates dendritic cell immune responses during the early phase of sepsis via RETREG1-mediated reticulophagy.

INTRODUCTION Interleukin-33 (IL-33) is a damage-associated alarmin that may have a profound effect on systemic inflammation. Dendritic cells (DCs) are critically involved in sepsis progression, but the precise regulation of DC function by IL-33 remains unresolved.

Objectives

This study explored the role of the IL-33 signaling axis in DCs activation during sepsis.

Methods

The role of IL-33 was investigated using an in vitro DC system and a cecal ligation and puncture-induced sepsis model in wild-type and interleukin-1 receptor-like 1 (IL-1RL1)-deficient mice. Downstream mechanisms were dissected through proteomic analysis, Western blotting, and genetic ablation. Validation was performed using mice deficient in reticulophagy regulator 1 (RETREG1) and activating transcription factor 6 (ATF6), as well as with the inhibitor of calcium/calmodulin-dependent kinase II (CaMKII).

Results

IL-33 stimulation potently enhanced DC function in an IL-1RL1-dependent manner. IL-33 promoted RETREG1-mediated reticulophagy, a process essential for DC activation, as DCs from Retreg1-/- mice showed markedly attenuated activation responses. Mechanistically, IL-33 induced the nuclear translocation of ATF6, a transcription factor implicated in RETREG1 regulation. Concurrently, IL-33 activated CaMKII, which was associated with increased RETREG1 phosphorylation, thereby potentiating RETREG1-driven reticulophagy.

Conclusion

Our findings unveil a novel pathway wherein IL-33 orchestrates DC immune function during early sepsis through a dual mechanism-transcriptional upregulation and functional potentiation of RETREG1. Modulation of IL-33/RETREG1-mediated reticulophagy may inform therapeutic development for septic complications.