Authors
Lux, C., Kahveci-Tuerkoez, S., Schun, K., Babendreyer, A., Martin, C., Kasparek, P., Sedlacek, R., Duesterhoeft, S., Ludwig, A.
Abstract
ADAM17 sheds cell surface molecules such as TNF-, IL-6R and L-selectin. This activity requires either iRhom1 or iRhom2 as adapter molecules. Since iRhom2 is predominantly expressed in leukocytes and upregulated in tissue cells during inflammation, it represents a potential anti-inflammatory target. We therefore investigated the effects of iRhom2 deficiency in mice using in vivo, ex vivo, and in vitro models of acute inflammation. In an in vivo model of LPS-induced lung inflammation, iRhom2 knockout mice showed reduced neutrophil recruitment into the bronchoalveolar space. Notably, the few recruited neutrophils remained L-selectin positive, whereas most neutrophils in wildtype mice were L-selectin negative, confirming that L-selectin shedding depends on the iRhom2/ADAM17 axis. Furthermore, it suggests that impaired shedding is associated with decreased neutrophil recruitment. Additionally, ADAM17-dependent release of TNF- and IL-6R into the alveolar space was diminished in the absence of iRhom2, accompanied by reduced expression of inflammatory mediators. In isolated perfused lungs challenged with LPS, iRhom2 deficiency similarly reduced inflammatory mediator production, indicating a role for iRhom2 in resident lung tissue cells during the initiation of inflammation. To specifically assess immune cell responses, we further examined macrophages, the sole resident immune cells in the lung. In vitro, LPS-stimulated bone marrow derived macrophages lacking iRhom2 showed decreased shedding of TNF- and IL-6R and reduced induction of secondary inflammatory mediators. Thus, targeting iRhom2 effectively suppresses ADAM17-mediated inflammatory responses in the lung, while preserving basal ADAM17 activity through iRhom1, offering a more selective therapeutic strategy with fewer side effects.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 10 Jun 2026.
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