Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

Abstract

Deciphering the molecular basis of leukocyte recruitment is critical to the understanding of inflammation. In this study, we investigated the contribution of the tetraspanin CD37 to this key process. CD37-deficient mice showed impaired neutrophil recruitment in a peritonitis model. Intravital microscopic analysis indicated that the absence of CD37 impaired the capacity of leukocytes to follow a CXCL1 chemotactic gradient accurately in the interstitium. Moreover, analysis of CXCL1-induced leukocyte-endothelial cell interactions in postcapillary venules revealed that CXCL1-induced neutrophil adhesion and transmigration were reduced in the absence of CD37, consistent with a reduced capacity to undergo β2 integrin–dependent adhesion. This result was supported by in vitro flow chamber experiments that demonstrated an impairment in adhesion of CD37-deficient neutrophils to the β2 integrin ligand, ICAM-1, despite the normal display of high-affinity β2 integrins. Superresolution microscopic assessment of localization of CD37 and CD18 in ICAM-1–adherent neutrophils demonstrated that these molecules do not significantly cocluster in the cell membrane, arguing against the possibility that CD37 regulates β2 integrin function via a direct molecular interaction. Moreover, CD37 ablation did not affect β2 integrin clustering. In contrast, the absence of CD37 in neutrophils impaired actin polymerization, cell spreading and polarization, dysregulated Rac-1 activation, and accelerated β2 integrin internalization. Together, these data indicate that CD37 promotes neutrophil adhesion and recruitment via the promotion of cytoskeletal function downstream of integrin-mediated adhesion.

Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas

“…Although its biologic function is incompletely understood, CD37 is involved in various different cellular processes, including survival, proliferation, adhesion, and migration of lymphocytes. [12][13][14][15][16] CD37 expression is restricted to lymphoid tissues, and in particular to mature B cells, with low levels of expression on plasma cells and dendritic cells. 17,18 This pattern is mirrored in B-cell malignancies: it is expressed in mature B-cell neoplasms, including mantle cell lymphoma (MCL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, and chronic lymphocytic leukemia (CLL), whereas it is low or absent in ALL and multiple myeloma.…”

Non‐IgE mediated mast cell activation

“…On the other hand, cultured human MCs, whereas positive for tetraspanins CD53, CD63, and CD81, do not express CD37 . CD37 mediates apoptotic signals in B cells and regulates β2 integrin‐mediated adhesion and migration of neutrophils …”

Crystal Structure of a Full-Length Human Tetraspanin Reveals a Cholesterol-Binding Pocket

“…There is accumulating evidence that the six tetraspanins in the C8 subclass regulate Notch signaling by promoting ADAM10 trafficking and enzymatic maturation in both flies and mammals (Dornier et al, 2012; Haining et al, 2012; Jouannet et al, 2016; Noy et al, 2016). A number of other tetraspanins appear to exert their effects by influencing integrin signaling, either indirectly by modulating responses of integrins to their ligands (van Spriel et al, 2012; Wee et al, 2015), or by directly and stably associating with particular integrin heterodimers (Yauch et al, 1998). Moreover, knockout of CD37 in mice predisposes them to development of B-cell lymphoma, a phenotype attributed to unrestrained IL-6 signaling in the absence of CD37 (de Winde et al, 2016).…”