Study Identifies iRhom2 as Key Driver of Acute Lung Inflammation, Potential Drug Target
A new preprint study using mouse models found that deleting the protein iRhom2 significantly reduced acute lung inflammation triggered by bacterial endotoxin (LPS). iRhom2 acts as an adapter molecule for ADAM17, an enzyme that releases pro-inflammatory signals including TNF-α and IL-6R from cell surfaces. The findings suggest that selectively targeting iRhom2 could suppress harmful lung inflammation while leaving baseline protective immune functions intact.
Researchers publishing on bioRxiv investigated the role of iRhom2, a pseudoproteinase that regulates the inflammatory enzyme ADAM17, in acute lung inflammation. Using iRhom2 knockout mice exposed to LPS — a model of bacterial-driven lung injury — they observed substantially fewer neutrophils recruited into the bronchoalveolar space compared to normal mice. The neutrophils that did appear in knockout mice retained L-selectin on their surface, a marker typically shed during activation, confirming that iRhom2 and ADAM17 together drive this shedding process and that impaired shedding correlates with reduced neutrophil recruitment. Release of TNF-α and IL-6R into the alveolar space was also diminished in knockout animals, along with broader reductions in inflammatory mediator expression. Experiments in isolated perfused lungs and in LPS-stimulated bone marrow-derived macrophages reproduced these findings, indicating iRhom2 plays a role in both resident lung tissue cells and immune cells. Because a related protein, iRhom1, can maintain baseline ADAM17 activity in the absence of iRhom2, the authors argue that targeting iRhom2 specifically could offer anti-inflammatory benefits with fewer systemic side effects than broader ADAM17 inhibition.
What's missing
As a preprint, this study has not yet undergone peer review. The research is conducted entirely in mouse models, and it is unknown whether iRhom2 plays a comparable role in human lung inflammation. The study does not address potential compensatory mechanisms that might limit therapeutic efficacy over time, nor does it report pharmacological inhibition of iRhom2 — only genetic knockout — leaving the translational pathway to drug development unclear. Long-term safety implications of iRhom2 inhibition are not assessed.
What different sources said
- bioRxivCenter
The pseudoproteinase iRhom2 critically promotes acute lung inflammation
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