Guided Monocyte Fate to FRβ/CD163 S1 Macrophage Antagonises Atopic Dermatitis Via Fibroblastic Matrices in Mouse Hypodermis

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2024 Dec 25

PMID 39720957

Authors

Yu-Tung Li

Eiichi Takaki

Yuya Ouchi

Katsuto Tamai

Affiliations

Soon will be listed here.

Abstract

Macrophages are versatile myeloid leukocytes with flexible cellular states to perform diverse tissue functions beyond immunity. This plasticity is however often hijacked by diseases to promote pathology. Scanning kinetics of macrophage states by single-cell transcriptomics and flow cytometry, we observed atopic dermatitis drastically exhausted a resident subtype S1. Characterized by FRβ/CD163 expression, S1 exhibited strong efferocytosis and chemoattracted monocytes and eosinophils. Here we have delineated mechanisms regulating monocyte decision to acquire S1 identity in skin. During M-CSF driven macrophage differentiation in healthy skin, FRβ was expressed via intrinsic control of STAT6 and ALK5 activities, and did not require heterotypic cellular crosstalk. In contrast, CD163 expression required exposure to fibroblastic secretion. This process depended on SHP1 activity and involved STAT5 inactivation. Suppressed STAT5 activity caused CD163 expression and rendered macrophage insensitive to further induction by fibroblasts. Parsing coculture experiments with in silico ligand expression, we identified laminin-α2 and type-V collagen secreted by hypodermal fibroblasts as CD163-driving factors. S1 identity loss in AD followed a stepwise cascade: reduced laminins availability first dampened CD163 expression, IL4 and TGFβ subsequently acted on CD163 cells to downregulate FRβ. In AD skin, we showed that imitating this fibroblast-macrophage crosstalk with exogenous laminin-211 encouraged monocyte differentiation to S1 macrophages, fostered homeostatic commitment of extravasated eosinophils, and alleviated dermatitis. Hence, we demonstrated that reinforcing a steady-state cue from hypodermal fibroblasts could override maladaptive pressure on macrophage and restored tissue homeostasis.

References

Ramalingam T, Pesce J, Sheikh F, Cheever A, Mentink-Kane M, Wilson M . Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor alpha1 chain. Nat Immunol. 2007; 9(1):25-33. PMC: 2692551. DOI: 10.1038/ni1544. View

Badia-I-Mompel P, Velez Santiago J, Braunger J, Geiss C, Dimitrov D, Muller-Dott S . decoupleR: ensemble of computational methods to infer biological activities from omics data. Bioinform Adv. 2023; 2(1):vbac016. PMC: 9710656. DOI: 10.1093/bioadv/vbac016. View

Hulsmans M, Clauss S, Xiao L, Aguirre A, King K, Hanley A . Macrophages Facilitate Electrical Conduction in the Heart. Cell. 2017; 169(3):510-522.e20. PMC: 5474950. DOI: 10.1016/j.cell.2017.03.050. View

Suzuki T, Arumugam P, Sakagami T, Lachmann N, Chalk C, Sallese A . Pulmonary macrophage transplantation therapy. Nature. 2014; 514(7523):450-4. PMC: 4236859. DOI: 10.1038/nature13807. View

Tjin M, Chua A, Moreno-Moral A, Chong L, Tang P, Harmston N . Biologically relevant laminin as chemically defined and fully human platform for human epidermal keratinocyte culture. Nat Commun. 2018; 9(1):4432. PMC: 6207750. DOI: 10.1038/s41467-018-06934-3. View

Renert-Yuval Y, Thyssen J, Bissonnette R, Bieber T, Kabashima K, Hijnen D . Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council. J Allergy Clin Immunol. 2021; 147(4):1174-1190.e1. PMC: 11304440. DOI: 10.1016/j.jaci.2021.01.013. View

Cook M, Jarjour N, Lin C, Edelson B . Transcription Factor Bhlhe40 in Immunity and Autoimmunity. Trends Immunol. 2020; 41(11):1023-1036. PMC: 7606821. DOI: 10.1016/j.it.2020.09.002. View

Holland C, Szalai B, Saez-Rodriguez J . Transfer of regulatory knowledge from human to mouse for functional genomics analysis. Biochim Biophys Acta Gene Regul Mech. 2019; 1863(6):194431. DOI: 10.1016/j.bbagrm.2019.194431. View

Sandberg M, Sutton S, Pletcher M, Wiltshire T, Tarantino L, Hogenesch J . c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev Cell. 2005; 8(2):153-66. DOI: 10.1016/j.devcel.2004.12.015. View

10.

Mishra M, Rawji K, Keough M, Kappen J, Dowlatabadi R, Vogel H . Harnessing the Benefits of Neuroinflammation: Generation of Macrophages/Microglia with Prominent Remyelinating Properties. J Neurosci. 2021; 41(15):3366-3385. PMC: 8051677. DOI: 10.1523/JNEUROSCI.1948-20.2021. View

11.

Li Y, Yamazaki S, Takaki E, Ouchi Y, Kitayama T, Tamai K . PDGFRα-lineage origin directs monocytes to trafficking proficiency to support peripheral immunity. Eur J Immunol. 2021; 52(2):204-221. PMC: 9299050. DOI: 10.1002/eji.202149479. View

12.

Weidinger S, Beck L, Bieber T, Kabashima K, Irvine A . Atopic dermatitis. Nat Rev Dis Primers. 2018; 4(1):1. DOI: 10.1038/s41572-018-0001-z. View

13.

Paolicelli R, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P . Synaptic pruning by microglia is necessary for normal brain development. Science. 2011; 333(6048):1456-8. DOI: 10.1126/science.1202529. View

14.

Cheung M, Erman E, Moore K, Lever J, Li Z, LaFontaine J . Resident macrophage subpopulations occupy distinct microenvironments in the kidney. JCI Insight. 2022; 7(20). PMC: 9714795. DOI: 10.1172/jci.insight.161078. View

15.

Chojnacki A, Wojcik K, Petri B, Aulakh G, Jacobsen E, LeSuer W . Intravital imaging allows real-time characterization of tissue resident eosinophils. Commun Biol. 2019; 2:181. PMC: 6513871. DOI: 10.1038/s42003-019-0425-3. View

16.

Diny N, Schonfeldova B, Shapiro M, Winder M, Varsani-Brown S, Stockinger B . The aryl hydrocarbon receptor contributes to tissue adaptation of intestinal eosinophils in mice. J Exp Med. 2022; 219(4). PMC: 8899390. DOI: 10.1084/jem.20210970. View

17.

Barreiro O, Cibrian D, Clemente C, Alvarez D, Moreno V, Valiente I . Pivotal role for skin transendothelial radio-resistant anti-inflammatory macrophages in tissue repair. Elife. 2016; 5. PMC: 4961461. DOI: 10.7554/eLife.15251. View

18.

Christofides A, Konstantinidou E, Jani C, Boussiotis V . The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism. 2020; 114:154338. PMC: 7736084. DOI: 10.1016/j.metabol.2020.154338. View

19.

Browaeys R, Saelens W, Saeys Y . NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods. 2019; 17(2):159-162. DOI: 10.1038/s41592-019-0667-5. View

20.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View