Neutrophil microtubules suppress polarity and enhance directional migration

Xu, Jingsong; Wang, Fei; Keymeulen, Alexandra Van; Rentel, Maike; Bourne, Henry R.

doi:10.1073/pnas.0502106102

Cited by 121 publications

(160 citation statements)

References 40 publications

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“…6a,b, Supplementary Note 6,7 and Supplementary Fig. 6), consistent with previous observations on neutrophils 29 and lymphocytes 30 . Perturbation of cell polarity by nocodazole is clearly revealed by the much wider shape of the lamellipod that tends to extend in 360°directions ( Fig.…”

Section: Cells Can Navigate Under Passive Wind Vane Self-steeringsupporting

confidence: 80%

Lymphocytes can self-steer passively with wind vane uropods

et al. 2014

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A wide variety of cells migrate directionally in response to chemical or mechanical cues, however the mechanisms involved in cue detection and translation into directed movement are debatable. Here we investigate a model of lymphocyte migration on the inner surface of blood vessels. Cells orient their migration against fluid flow, suggesting the existence of an adaptive mechano-tranduction mechanism. We find that flow detection may not require molecular mechano-sensors of shear stress, and detection of flow direction can be achieved by the orientation in the flow of the non-adherent cell rear, the uropod. Uropods act as microscopic wind vanes that can transmit detection of flow direction into cell steering via the on-going machinery of polarity maintenance, without the need for novel internal guidance signalling triggered by flow. Contrary to chemotaxis, which implies active regulation of cue-dependent signalling, upstream flow mechanotaxis of lymphocytes may only rely on a passive self-steering mechanism.

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Section: Cells Can Navigate Under Passive Wind Vane Self-steeringsupporting

confidence: 80%

Lymphocytes can self-steer passively with wind vane uropods

et al. 2014

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“…S2 and S3). Five of these drugs are compounds that inhibit microtubule polymerization, which is consistent with recent reports indicating that microtubules negatively regulate uropod signaling and enhance directional sensing in neutrophils (10,11). Interestingly, the most dramatic inhibitory effect was induced by diphenyleneiodonium chloride (DPI), a well characterized and commonly used flavoprotein inhibitor that was known to suppress activity of NADPH oxidase and NOS (12)(13)(14).…”

Section: Resultssupporting

confidence: 65%

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis

Hattori

Subramanian

Sakai

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Neutrophil chemotaxis plays an essential role in innate immunity, but the underlying cellular mechanism is still not fully characterized. Here, using a small-molecule functional screening, we identified NADPH oxidase–dependent reactive oxygen species as key regulators of neutrophil chemotactic migration. Neutrophils with pharmacologically inhibited oxidase, or isolated from chronic granulomatous disease (CGD) patients and mice, formed more frequent multiple pseudopodia and lost their directionality as they migrated up a chemoattractant concentration gradient. Knocking down NADPH oxidase in differentiated neutrophil-like HL60 cells also led to defective chemotaxis. Consistent with the in vitro results, adoptively transferred CGD murine neutrophils showed impaired in vivo recruitment to sites of inflammation. Together, these results present a physiological role for reactive oxygen species in regulating neutrophil functions and shed light on the pathogenesis of CGD.

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“…For these experiments we treated neutrophils with the myosin II inhibitor blebbistatin (100 M) or the ROCK inhibitor Y-27632 (10 M) and assessed fMLP-mediated AC activation. As published previously, we found that both treatments gave rise to cells with multiple pseudopods and a general lost of uropod (data not shown) (Niggli, 2003a;Xu et al, 2003;Xu et al, 2005). However, neither drugs affected the extent by which fMLP stimulates AC activity (Figure 4, E and F).…”

supporting

confidence: 65%

A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

Mahadeo

Janka-Junttila

Smoot

et al. 2007

MBoC

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Neutrophils and Dictyostelium use conserved signal transduction pathways to decipher chemoattractant gradients and migrate directionally. In both cell types, addition of chemoattractants stimulates the production of cAMP, which has been suggested to regulate chemotaxis. We set out to define the mechanism by which chemoattractants increase cAMP levels in human neutrophils. We show that chemoattractants elicit a rapid and transient activation of adenylyl cyclase (AC). This activation is sensitive to pertussis toxin treatment but independent of phosphoinositide-3 kinase activity and an intact cytoskeleton. Remarkably, and in sharp contrast to G␣ s -mediated activation, chemoattractant-induced AC activation is lost in cell lysates. Of the nine, differentially regulated transmembrane AC isoforms in the human genome, we find that isoforms III, IV, VII, and IX are expressed in human neutrophils. We conclude that the signal transduction cascade used by chemoattractants to activate AC is conserved in Dictyostelium and human neutrophils and is markedly different from the canonical G␣ s -meditated pathway. INTRODUCTIONMany types of cells have the ability to migrate directionally when exposed to gradients of chemoattractants. This chemotactic response is essential for a variety of physiological processes and is initiated when chemoattractants bind surface receptors and activate a wide range of signal transduction cascades, which ultimately lead to cellular polarization and migration (Parent, 2004). The acquisition of polarity is accompanied by a dramatic redistribution of cytoskeletal components, where F-actin and numerous actin-binding proteins are enriched at the front or leading edge and myosin II is assembled on the sides and at the back or trailing edge (Van Haastert and Devreotes, 2004;Bagorda et al., 2006).A striking chemotactic behavior is exhibited by neutrophils as they move across vascular barriers and navigate to sites of inflammation (Niggli, 2003b;Parent, 2004). The agents that induce directed migration of neutrophils include a large and diverse group of chemoattractants originating from different sources (Uhing and Snyderman, 1999). These agents include formylated peptides secreted by bacteria (such as N-formylmethionyl-leucyl-phenylalanine [fMLP]), products of the complement cascade (such as complement factor 5a [C5a]), and phospholipid metabolites (such as leukotriene B4 [LTB 4 ]) as well as a large family of chemokines that are derived from endothelial, epithelial, and stromal cells (Baggiolini, 1998). Remarkably, neutrophils can also relay the signal to surrounding cells by stimulating the production and release of more attractants, such as LTB 4 and interleukin (IL)-8, which act in a paracrine manner to spread the chemotactic response to surrounding cells (Bazzoni et al., 1991;Baggiolini et al., 1994;Kannan, 2002). Chemoattractants bind to serpentine transmembrane receptors that couple to heterotrimeric G proteins (Murphy, 1996). Receptor activation leads to the dissociation of the G protein into ␣-and...

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Neutrophil microtubules suppress polarity and enhance directional migration

Cited by 121 publications

References 40 publications

Lymphocytes can self-steer passively with wind vane uropods

Lymphocytes can self-steer passively with wind vane uropods

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis

A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

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Neutrophil microtubules suppress polarity and enhance directional migration

Cited by 121 publications

References 40 publications

Lymphocytes can self-steer passively with wind vane uropods

Lymphocytes can self-steer passively with wind vane uropods

Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis

A Chemoattractant-mediated Gi-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils

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A Chemoattractant-mediated G_i-coupled Pathway Activates Adenylyl Cyclase in Human Neutrophils