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Reply to 'Does neutrophil CD38 have a role in Ca++ signaling triggered by β2 integrin?'

Nature Medicine volume 8, pages 307–308 (2002)Cite this article

Lund et al. reply

Dewitt et al. question our claim that CD38-deficient mice are unable to respond to bacterial infections because Cd38−/− neutrophils cannot produce the cADPR and do not mobilize Ca++ normally or migrate directionally when stimulated with the bacterial chemo-attractant, fMLP (ref. 1). The authors point out that Cd38−/− neutrophils can respond to IL-8 (ref. 1) and therefore should be able to migrate to the site of infection. However, mice lacking the N-formyl peptide receptor have the capacity to make and respond to IL-8, yet are highly susceptible to bacterial infections11. Thus, formylated peptides released at the site of infection are critical chemoattractants for neutrophils in vivo. The authors also state that Ca++ mobilization in fMLP-stimulated neutrophils is IP3 dependent4 and can be uncoupled from chemotaxis. In addition to IP3, cADPR and sphingosine-1-phosphate (SPP) mediate intracellular Ca++ release in fMLP-stimulated neutrophils1,12. We and others13,14 argue that free cytosolic Ca++, released by IP3 or SPP, in combination with cADPR induces Ca++ release from ryanodine-receptor stores in a process referred to as calcium-induced calcium release. Furthermore, we showed that extracellular Ca++ influx in response to fMLP is absolutely dependent on the calcium-induced calcium release response controlled by cADPR and presumably ryanodine receptors1,15. Thus, Ca++ mobilization in fMLP-stimulated neutrophils is highly complex and involves several different second messengers. Finally, mouse bone-marrow neutrophils that lack either IP3 or cADPR make poor chemotactic responses to fMLP, thus Ca++ release is coupled to chemotaxis for at least this subset of nonelicited and unprimed neutrophils1,16,17. Therefore, we believe that our model offers a convincing explanation for our data; however, we do not dispute the possibility that CD38-deficient neutrophils could be defective in other functional assays. Thus, if β2 integrin–induced Ca++ release is shown to be cADPR dependent, it would represent a good candidate for another CD38-dependent signaling process in neutrophils.

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  1. Trudeau Institute, Saranac Lake, New York, USA

    Frances E. Lund, Troy D. Randall & Santiago Partida-Sánchez

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Lund, F., Randall, T. & Partida-Sánchez, S. Reply to 'Does neutrophil CD38 have a role in Ca++ signaling triggered by β2 integrin?'. Nat Med 8, 307–308 (2002). https://doi.org/10.1038/nm0402-307b

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