Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing

Mills, Stuart J.; Ahangar, Parinaz; Thomas, Hannah M.; Hofma, Benjamin R.; Murray, Rachael Z.; Cowin, Allison J.

doi:10.3390/cells11142192

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Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing

by

Stuart J. Mills

^1,*,

Parinaz Ahangar

¹

,

Hannah M. Thomas

¹,

Benjamin R. Hofma

¹,

Rachael Z. Murray

^2,†

and

Allison J. Cowin

^1,*,†

¹

Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, Adelaide SA 5095, Australia

²

School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane QLD 4059, Australia

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this paper.

Cells 2022, 11(14), 2192; https://doi.org/10.3390/cells11142192

Submission received: 9 June 2022 / Revised: 6 July 2022 / Accepted: 8 July 2022 / Published: 13 July 2022

(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)

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Abstract

TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is an immunomodulator that negatively regulates macrophage TLR4 signalling. Using macrophages from Flii^+/−, WT, and Flii^Tg/Tg mice, we have shown that elevated Flii reduces early TLR4 surface expression, delaying and reducing subsequent TNF secretions. In contrast, reduced Flii increases surface TLR4, leading to an earlier robust TNF peak. In Flii^+/− mice, TLR4 levels peak earlier during wound repair, and overall healing is accelerated. Fewer neutrophils, monocytes and macrophages are recruited to Flii^+/− wounds, leading to fewer TNF-positive macrophages, alongside an early peak and a robust shift to M2 anti-inflammatory, reparative Ym1⁺ and IL-10⁺ macrophages. Importantly, in diabetic mice, high Flii levels are found in plasma and unwounded skin, with further increases observed in their wounds, which have impaired healing. Lowering Flii in diabetic mice results in an earlier shift to M2 macrophages and improved healing. Overall, this suggests Flii regulation of TLR4 reduces early inflammation and decreases the M2 macrophage phenotype, leading to impaired healing.

Keywords: Flightless I; inflammation; macrophage; toll-like receptor (TLR4); skin; wound healing

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MDPI and ACS Style

Mills, S.J.; Ahangar, P.; Thomas, H.M.; Hofma, B.R.; Murray, R.Z.; Cowin, A.J. Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing. Cells 2022, 11, 2192. https://doi.org/10.3390/cells11142192

AMA Style

Mills SJ, Ahangar P, Thomas HM, Hofma BR, Murray RZ, Cowin AJ. Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing. Cells. 2022; 11(14):2192. https://doi.org/10.3390/cells11142192

Chicago/Turabian Style

Mills, Stuart J., Parinaz Ahangar, Hannah M. Thomas, Benjamin R. Hofma, Rachael Z. Murray, and Allison J. Cowin. 2022. "Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing" Cells 11, no. 14: 2192. https://doi.org/10.3390/cells11142192

APA Style

Mills, S. J., Ahangar, P., Thomas, H. M., Hofma, B. R., Murray, R. Z., & Cowin, A. J. (2022). Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing. Cells, 11(14), 2192. https://doi.org/10.3390/cells11142192

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

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Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing

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