scholarly journals Decision letter: Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells

2018 ◽  
eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eva Plesch ◽  
Cheng-Chang Chen ◽  
Elisabeth Butz ◽  
Anna Scotto Rosato ◽  
Einar K Krogsaeter ◽  
...  

Cytokines and chemokines are produced and secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators are released from the various immune cells. Here, the endolysosomal cation channel TRPML2 is shown to play a direct role in chemokine trafficking and secretion from murine macrophages. To demonstrate acute and direct involvement of TRPML2 in these processes, the first isoform-selective TRPML2 channel agonist was generated, ML2-SA1. ML2-SA1 was not only found to directly stimulate release of the chemokine CCL2 from macrophages but also to stimulate macrophage migration, thus mimicking CCL2 function. Endogenous TRPML2 is expressed in early/recycling endosomes as demonstrated by endolysosomal patch-clamp experimentation and ML2-SA1 promotes trafficking through early/recycling endosomes, suggesting CCL2 being transported and secreted via this pathway. These data provide a direct link between TRPML2 activation, CCL2 release and stimulation of macrophage migration in the innate immune response.


Author(s):  
Eva Plesch ◽  
Cheng-Chang Chen ◽  
Elisabeth Butz ◽  
Anna Scotto Rosato ◽  
Einar K Krogsaeter ◽  
...  

2016 ◽  
Vol 397 (10) ◽  
pp. 1017-1029 ◽  
Author(s):  
Heiko Weyd

Abstract In more than 30 years of research annexins have been demonstrated to regulate immune responses. The prototype member of this family, annexin (Anx) A1, has been widely recognized as an anti-inflammatory mediator affecting migration and cellular responses of various cell types of the innate immune system. Evidently, effects on innate immune cells also impact on the course of adaptive immune responses. Innate immune cells provide a distinct cytokine milieu during initiation of adaptive immunity which regulates the development of T cell responses. Moreover, innate immune cells such as monocytes can differentiate into dendritic cells and take an active part in T cell stimulation. Accumulating evidence shows a direct role for annexins in adaptive immunity. Anx A1, the annexin protein studied in most detail, has been shown to influence antigen presentation as well as T cells directly. Moreover, immune modulatory roles have been described for several other annexins such as Anx A2, Anx A4, Anx A5 and Anx A13. This review will focus on the involvement of Anx A1 and other annexins in central aspects of adaptive immunity, such as recruitment and activation of antigen presenting cells, T cell differentiation and the anti-inflammatory removal of apoptotic cells.


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