Editors' ChoiceImmunology

Arresting migrating neutrophils with ROS

Sci. Signal.  04 Oct 2016:
Vol. 9, Issue 448, pp. ec226
DOI: 10.1126/scisignal.aal1285

Upon reaching sites of infection or injury, neutrophils must stop migrating and start producing inflammatory responses, one of which involves the generation of reactive oxygen species (ROS). TRPM2 is a cation channel that is involved in inflammatory responses and that can be activated by ROS. Wang et al. determined the role of TRPM2 in migrating neutrophils. Inflammatory responses and neutrophil accumulation were greater in skin lesions induced by application of the bacterial molecule lipopolysaccharide (LPS) followed by the cytokine tumor necrosis factor–α (TNF-α) in Trpm2–/– mice than in those induced in wild-type mice. Similarly, in response to intratracheal injection of a bacterial formyl peptide [fMet-Leu-Phe (fMLF)], neutrophils accumulated to a greater extent in the lungs of Trpm2–/– mice than in those of wild-type mice. Compared with wild-type neutrophils, Trpm2–/– neutrophils showed enhanced directed migration in response to a gradient of formylMet-Ile-Phe-Leu (fMILF), as well as those of other attractants, such as complement component C5a and interleukin-8. The enhanced directed migration in Trpm2–/– neutrophils in response to the fMILF gradient did not require the channel function of TRPM2 or involve changes in Ca2+ signaling. fMLF induced the internalization of its receptor FPR1 in wild-type neutrophils, as expected, but not in Trpm2–/– neutrophils. FRET (fluorescence resonance energy transfer) analysis indicated that, in unstimulated cells, overexpressed FPR1 and TRPM2 colocalized at the plasma membrane and that fMLF stimulation triggered the translocation of these proteins to the cytoplasm, an effect that required ROS production and Cys549 in TRPM2. Mass spectrometry indicated that exposing purified TRPM2 to H2O2 triggered the dioxidation and trioxidation of Cys549. Overexpression of a C549A TRPM2 mutant in HL60 cells (a human promyelocytic leukemia cell line) resulted in enhanced migration compared with those expressing wild-type TRPM2. Thus, ROS-mediated oxidation of Cys549 in TRPM2 appears to trigger the internalization of both this modified form of TRPM2 and receptors that respond to attractant signals to attenuate migration in neutrophils, which may enable migrating neutrophils to switch from migrating to producing inflammatory responses. In the associated commentary, Renkawitz and Sixt note that ROS are an attractive autoregulatory mechanism for attenuating inflammation because ROS generate much of the local tissue damage caused by inflammation.

G. Wang, L. Cao, X. Liu, N. A. Sieracki, A. Di, X. Wen, Y. Chen, S. Taylor, X. Huang, C. Tiruppathi, Y.-y. Zhao, Y. Song, X. Gao, T. Jin, C. Bai, A. B. Malik, J. Xu, Oxidant sensing by TRPM2 inhibits neutrophil migration and mitigates inflammation. Dev. Cell 38, 453–462 (2016). [PubMed]

J. Renkawitz, M. Sixt, A radical break: Restraining neutrophil migration. Dev. Cell 38, 448–450 (2016). [PubMed]

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