The pseudoproteinase iRhom2 critically promotes acute lung inflammation

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. HighlightsO_LIThe ADAM17 adapter molecule iRhom2 is required for the acute lung inflammation of mice in vivo including cytokine response and neutrophil recruitment. C_LIO_LIIn resident lung tissue cells iRhom2 promotes the LPS induced inflammatory response at the alveolar interface. C_LIO_LIIn macrophages iRhom2 is required for an effective ADAM17 dependent inflammatory response to LPS. C_LIO_LIThus, iRhom2 targeting can serve to suppress inflammatory activities of ADAM17 in the lung. C_LI Graphical AbstractSchematic overview depicting the role of the iRhom2-ADAM17 axis in mediating neutrophil infiltration and cytokine release during induced pulmonary inflammation, serving as a model for acute lung injury (ALI). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/730404v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@d7edc9org.highwire.dtl.DTLVardef@3c4654org.highwire.dtl.DTLVardef@12d36f8org.highwire.dtl.DTLVardef@173dc97_HPS_FORMAT_FIGEXP M_FIG C_FIG