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Tissue damage detection by osmotic surveillance

Nature Cell Biology volume 15, pages 1123–1130 (2013)Cite this article

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Abstract

How tissue damage is detected to induce inflammatory responses is unclear. Most studies have focused on damage signals released by cell breakage and necrosis1. Whether tissues use other cues in addition to cell lysis to detect that they are damaged is unknown. We find that osmolarity differences between interstitial fluid and the external environment mediate rapid leukocyte recruitment to sites of tissue damage in zebrafish by activating cytosolic phospholipase a2 (cPLA2) at injury sites. cPLA2 initiates the production of non-canonical arachidonate metabolites that mediate leukocyte chemotaxis through a 5-oxo-ETE receptor (OXE-R). Thus, tissues can detect damage through direct surveillance of barrier integrity, with cell swelling probably functioning as a pro-inflammatory intermediate in the process.

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Figure 1: Hypotonicity is required for rapid leukocyte recruitment to larval zebrafish tail fin wounds.
Figure 2: Hypotonicity locally activates cPLA2 at the wound site.
Figure 3: Extracellular Ca2+ is required for cPLA2 activation.
Figure 4: cPLA2 is required for rapid leukocyte recruitment to larval zebrafish tail fin wounds.
Figure 5: OXE-R is required for rapid leukocyte recruitment to larval zebrafish tail fin wounds.

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Acknowledgements

We thank T. Mitchison, A. Hall, M. Overholtzer and A. Kapus for their valuable thoughts and suggestions on the manuscript. This work was supported by NIH grant GM099970 and an L. V. Gerstner Young Investigator award.

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Authors and Affiliations

  1. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    Balázs Enyedi, Snigdha Kala, Tijana Nikolich-Zugich & Philipp Niethammer

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Contributions

P.N. conceived the project. B.E. and P.N. designed the experiments. B.E., P.N., S.K. and T.N-Z. carried out the experiments. P.N. and B.E. wrote the paper.

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Correspondence to Philipp Niethammer.

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Integrated supplementary information

Supplementary Figure 1 Isotonic inhibition of leukocyte recruitment is reversible and is not a result of necrosis or cytoplasmic leakage.

(a) Schematic diagram of experimental design. Larvae are wounded within a small volume (100–200 μl) of isotonic low melting agarose and imaged for 10 min. 3 ml of ‘isotonic’ (i, 145 mM NaCl) or hypotonic medium (h, 5 mM NaCl) are then added on top of the isotonic agar pad, and wound recruitment of leukocytes within t = 60 min after medium addition is quantified by light transmission microscopy (that is, allowing 20 min for equilibration of salt concentration throughout the agar pad as compared with our standard t = 40 min assays). Rapidly migrating cells (which correspond to leukocytes) are highlighted with coloured tracks. (b) Left: representative time-lapse images of wound recruitment after shifting the medium in which the larvae were wounded from isotonic to either hypotonic medium (‘i → h’ shift) or isotonic medium (‘i → i’ shift). Right: quantification of leukocyte recruitment within 60 min after tonicity shift. The number of larvae (n) used for the analyses is given in parentheses on the graphs. Error bars, s.e.m. **t-test p<0.005. Scale bar, 100 μm. (c) Staining of necrotic cells with Sytox Orange. Larvae were wounded in either hypotonic (h) or isotonic medium supplemented with 1 μM Sytox Orange. Necrosis was quantified as the area of Sytox-fluorescent cells at the wound site at t = 40 min after injury. Scale bar, 100 μm. (d) Leukocyte recruitment (within 40 min) in response to tail fin incisions in hypotonic (h) or isotonic (i) medium in the presence or absence of 5 μM AA, 0.5 and 5 mM ATP or cytoplasm extract from Caco-2 cells (see Methods for details). The number of larvae (n) used for the analyses is given in parentheses on the graphs. Error bars, s.e.m. ***t-test p<0.0005.

Supplementary Figure 2 (a) cpla2 mRNA expression in leukocyte versus non-leukocyte tissue.

Leukocyte/non-leukocyte total mRNA was generated by FACS of dissociated, transgenic zebrafish larvae expressing a red fluorescent protein (mKate2) under the control of the lysC promoter. cpla2 mRNA expression between these samples was compared by semiquantitative RT–PCR. (b) Immunofluorescence staining of cPLA2 in intact and wounded wt, cpla2 morphant and cPLA2–mKate2 overexpressing larvae (expression of the latter shown in red). Scale bar, 10 μm. (c) Average leukocyte recruitment after hypotonic tail fin wounding of wt, cpla2 morphant or cpla2 morphant larvae that have been co-injected with mRNA encoding cPLA2–mKate2 for rescue. Data for the wt and cpla2 morphant larvae derive from the same data set as shown in Fig. 4a. (d) Average leukocyte recruitment after hypotonic tail fin wounding in the presence of 20 μM non-selective PLA2 inhibitor ACA). The number of larvae (n) used for the analyses is given in parentheses on the graphs. Error bars, s.e.m. *** t-test p<0.0005.

Supplementary Figure 3 Lipoxygenases, but not prostaglandins or canonical leukotrienes, are involved in wound recruitment of leukocytes.

Average recruitment of leukocytes after hypotonic tail fin wounding in the presence of (a) 20 μM MK-886 (ALOX inhibitor, more selective for ALOX5), 20 μM EDBC (ALOX inhibitor, more selective for ALOX12/15), (b) 100 μM bestatin (LTA4H inhibitor), or 20 μM Zileuton (ALOX inhibitor, more selective for ALOX5). (c) Average recruitment of leukocytes after tail fin wounding at indicated tonicity in the presence/absence of 15 μM AA and 100 μM acetylsalicylic acid (ASA, cyclooxygenase inhibitor). (d) Average recruitment of leukocytes after isotonic tail fin wounding in the presence/absence of 15 μM AA and 100 μM bestatin. (e) Average recruitment of leukocytes after hypotonic tail fin wounding of wt or lta4h morphant larvae, using a previously published translation targeting morpholino48. (f) alox5 mRNA expression in leukocyte versus non-leukocyte tissue. Leukocyte/non-leukocyte total mRNA was generated by FACS of dissociated, transgenic zebrafish larvae expressing a red fluorescent protein (mKate2) under the control of the lysC promoter. alox5 mRNA expression between these samples was compared by semiquantitative RT–PCR. The number of larvae (n) used for the analyses is given in parentheses on the graphs. Error bars, s.e.m. *t-test p<0.05. **t-test p<0.005. ***t-test p<0.0005.

Supplementary Figure 4 (a) Average recruitment and migratory parameters of leukocytes after hypotonic wounding of larvae that had, or had not, been pretreated with 5-KETE.

For OXE-R desensitization, larvae were soaked for 90 min in 2 μM 5-KETE before wounding. 5-KETE was washed out, and leukocyte recruitment to hypotonic wounds was measured in treated and non-treated samples. (b) Average recruitment of leukocytes within 40 min after isotonic tail fin wounding of wt or oxer1 morphant larvae in the presence of 5 μM AA in the medium. (c) Average recruitment of leukocytes within 40 min after hypotonic tail fin wounding of p53 morphant and p53+oxer1 morphant embryos. (d) oxer1 mRNA expression in leukocyte versus non-leukocyte tissue. Leukocyte/non-leukocyte total mRNA was generated by FACS of dissociated, transgenic zebrafish larvae expressing a red fluorescent protein (mKate2) under the control of the lysC promoter. oxer1 mRNA expression between these samples was compared by semiquantitative RT–PCR. (e) HyPer imaging of wound margin H2O2 production in response to wounding wt, cpla2 morphant and oxer1 morphant larvae. Top: representative HyPer-ratio images. Red, high [H2O2]. Blue, low [H2O2]. Bottom: normalized HyPer ratio as a function of time after wounding. The number of larvae (n) used for the analyses is given in parentheses on the graphs. Error bars, s.e.m. NS, t-test p>0.05. *t-test p<0.05. **t-test p<0.005. ***t-test p<0.0005. Scale bar, 100 μm.

Supplementary Figure 5 (a) Two paradigms of tissue damage detection.

Left: classic ‘cell-integrity paradigm’: Passive leakage of cytoplasmic DAMPs from broken cells produces leukocyte necrotaxis. Right: ‘tissue-integrity paradigm’: Epithelial barrier breakage induces cell swelling and de novo production of chemoattractants that attract leukocytes. (b) Schematic diagram of proposed regulatory circuits. Black arrows, mechanisms proposed by this study. Grey arrows, mechanisms proposed by previous studies (see references 14,29,34,37). Dashed grey arrows, speculative mechanisms.

Supplementary information

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Supplementary Information (PDF 651 kb)

Hypotonicity is required for rapid leukocyte recruitment to larval zebrafish tail fin wounds.

This movie shows leukocyte recruitment after tail fin wounding of wt larvae in hypotonic (control) or isotonic (145 mM NaCl) medium. Imaging starts ∼ 3 min pw (60 s per frame). Scale bar, 100 μm. (MOV 2046 kb)

Isotonicity reversibly inhibits rapid leukocyte recruitment to larval zebrafish tail fin wounds.

This movie shows leukocyte recruitment after tail fin wounding of wt larvae in isotonic medium that was shifted to hypotonic medium (‘i → h’ shift) or isotonic medium (‘i → i’ shift). Imaging starts ∼ 3 min pw (30 sec per frame). Scale bar, 100 μm. (MOV 2821 kb)

Hypotonicity locally activates cPLA2 at the wound site.

This movie montage shows cPLA2–mKate2 translocation to the nuclear membrane induced by UV-laser wounding in hypotonic (hypo), isotonic (iso) or hypotonic medium supplemented with 500 μM Gd3+(hypo+Gd3+). Laser wounding at ∼ 1 min (15 sec per frame). Scale bar, 100 μm. (MOV 2392 kb)

Gd3+ exposure enhances wound margin swelling.

This movie shows leukocyte recruitment after hypotonic tail fin wounding of WT larvae in the presence or absence of 500 μM Gd3+. Imaging starts ∼ 3 min pw, Gd3+ added at 0 min (60 sec per frame). Scale bar, 100 μm. (MOV 3597 kb)

Extracellular Ca2+ is required for cPLA2 activation.

This movie montage shows cPLA2–mKate2 translocation to the nuclear membrane induced by calcium-switch in hypotonic medium. Hypotonic Ca2+-free medium supplemented with 1mM EGTA was added at 0 min to the larvae that were prewounded in isotonic medium with EGTA. Larve were imaged for 40 min with (A, C) or without (B) re-addition of Ca2+ at 5 min. Movies from different experiments. Low magnification scale bar, 100 μm; high magnification scale bar, 10 μm (15 sec per frame). (MOV 3401 kb)

Tail fin injury rapidly increases cytoplasmic [Ca2+ at the wound site irrespective of medium tonicity.

This movie shows the cytosolic Ca2+ signal induced by UV-laser wounding of larval zebrafish tail fins maintained in hypotonic (h) or isotonic (i) medium. Laser wounding at ∼ 19 sec (3 sec per frame). Scale bar, 100 μm. (MOV 1867 kb)

cPLA2 is required for rapid leukocyte recruitment to larval zebrafish tail fin wounds.

This movie shows leukocyte recruitment in cpla2 morphant larva (cpla2 MO) versus WT larva 3dpf. Imaging starts ∼ 3 min pw (60 sec per frame). Scale bar, 100 μm. (MOV 2450 kb)

5-KETE is a chemoattractant for leukocytes in zebrafish.

This movie shows leukocyte recruitment after isotonic tail fin wounding of WT larvae in the presence or absence of 2 μM 5-KETE (5-oxo-ETE). Imaging starts ∼ 3 min pw, 5-KETE added at 0 min (60 sec per frame). Scale bar, 100 μm. (MOV 3097 kb)

OXE-R is required for rapid leukocyte recruitment to larval zebrafish tail fin wounds.

This movie shows leukocyte recruitment in oxer1 morphant larva (oxer1 MO) versus WT larva 3dpf. Imaging starts ∼ 3 min pw (60 sec per frame). Scale bar, 100 μm. (MOV 2005 kb)

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Enyedi, B., Kala, S., Nikolich-Zugich, T. et al. Tissue damage detection by osmotic surveillance. Nat Cell Biol 15, 1123–1130 (2013). https://doi.org/10.1038/ncb2818

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