Human Intraepithelial Mast Cell Differentiation and Effector Function Are Directed by TGF-β Signaling

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2025 Jan 2

PMID 39744949

Authors

Tahereh Derakhshan

Eleanor Hollers

Alex Perniss

Tessa Ryan

Alanna McGill

Jonathan Hacker

Regan W Bergmark

Neil Bhattacharyya

Stella E Lee

Alice Z Maxfield

Rachel E Roditi

Lora Bankova

Kathleen M Buchheit

Tanya M Laidlaw

Joshua A Boyce

Daniel F Dwyer

Affiliations

Soon will be listed here.

Abstract

Mast cells (MCs) expressing a distinctive protease phenotype (MCTs) selectively expand within the epithelium of human mucosal tissues during type 2 (T2) inflammation. While MCTs are phenotypically distinct from subepithelial MCs (MCTCs), signals driving human MCT differentiation and this subset's contribution to inflammation remain unexplored. Here, we have identified TGF-β as a key driver of the MCT transcriptome in nasal polyps. We found that short-term TGF-β signaling alters MC cell surface receptor expression and partially recapitulated the in vivo MCT transcriptome, while TGF-β signaling during MC differentiation upregulated a larger number of MCT-associated transcripts. TGF-β inhibited the hallmark MCTC proteases chymase and cathepsin G at both the transcript and protein level, allowing selective in vitro differentiation of MCTs for functional study. We identified discrete differences in effector phenotype between in vitro-derived MCTs and MCTCs, with MCTs exhibiting enhanced proinflammatory lipid mediator generation and a distinct cytokine, chemokine, and growth factor production profile in response to both innate and adaptive stimuli, recapitulating functional features of their tissue-associated counterpart MC subsets. Thus, our findings support a role for TGF-β in promoting human MCT differentiation and identified a discrete contribution of this cell type to T2 inflammation.

References

Stevens W, Ocampo C, Berdnikovs S, Sakashita M, Mahdavinia M, Suh L . Cytokines in Chronic Rhinosinusitis. Role in Eosinophilia and Aspirin-exacerbated Respiratory Disease. Am J Respir Crit Care Med. 2015; 192(6):682-94. PMC: 4595675. DOI: 10.1164/rccm.201412-2278OC. View

Mishra A, Wang M, Pemmaraju V, Collins M, Fulkerson P, Abonia J . Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia. Gastroenterology. 2008; 134(1):204-14. PMC: 2654267. DOI: 10.1053/j.gastro.2007.10.002. View

Denney L, Byrne A, Shea T, Buckley J, Pease J, Herledan G . Pulmonary Epithelial Cell-Derived Cytokine TGF-β1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function. Immunity. 2015; 43(5):945-58. PMC: 4658339. DOI: 10.1016/j.immuni.2015.10.012. View

Derakhshan T, Samuchiwal S, Hallen N, Bankova L, Boyce J, Barrett N . Lineage-specific regulation of inducible and constitutive mast cells in allergic airway inflammation. J Exp Med. 2020; 218(1). PMC: 7953627. DOI: 10.1084/jem.20200321. View

Salib R, Kumar S, Wilson S, Howarth P . Nasal mucosal immunoexpression of the mast cell chemoattractants TGF-beta, eotaxin, and stem cell factor and their receptors in allergic rhinitis. J Allergy Clin Immunol. 2004; 114(4):799-806. DOI: 10.1016/j.jaci.2004.07.010. View

Batra V, Musani A, Hastie A, Khurana S, Carpenter K, Zangrilli J . Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-beta1, TGF-beta2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on alpha-smooth muscle actin and collagen III synthesis by primary.... Clin Exp Allergy. 2004; 34(3):437-44. DOI: 10.1111/j.1365-2222.2004.01885.x. View

Matsuzawa S, Sakashita K, Kinoshita T, Ito S, Yamashita T, Koike K . IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J Immunol. 2003; 170(7):3461-7. DOI: 10.4049/jimmunol.170.7.3461. View

Wahl S, Hunt D, Wakefield L, McCartney-Francis N, Wahl L, Roberts A . Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987; 84(16):5788-92. PMC: 298948. DOI: 10.1073/pnas.84.16.5788. View

Dougherty R, Sidhu S, Raman K, Solon M, Solberg O, Caughey G . Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma. J Allergy Clin Immunol. 2010; 125(5):1046-1053.e8. PMC: 2918406. DOI: 10.1016/j.jaci.2010.03.003. View

10.

Ordovas-Montanes J, Dwyer D, Nyquist S, Buchheit K, Vukovic M, Deb C . Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature. 2018; 560(7720):649-654. PMC: 6133715. DOI: 10.1038/s41586-018-0449-8. View

11.

Kumar M, Duraisamy K, Chow B . Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2). Cells. 2021; 10(5). PMC: 8146469. DOI: 10.3390/cells10051033. View

12.

Hsieh F, Sharma P, Gibbons A, Goggans T, Erzurum S, Haque S . Human airway epithelial cell determinants of survival and functional phenotype for primary human mast cells. Proc Natl Acad Sci U S A. 2005; 102(40):14380-5. PMC: 1242292. DOI: 10.1073/pnas.0503948102. View

13.

Lorentz A, Wilke M, Sellge G, Worthmann H, Klempnauer J, Manns M . IL-4-induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK1/2 and c-Fos. J Immunol. 2005; 174(11):6751-6. DOI: 10.4049/jimmunol.174.11.6751. View

14.

Breuss J, Gallo J, DeLisser H, Klimanskaya I, Folkesson H, Pittet J . Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci. 1995; 108 ( Pt 6):2241-51. DOI: 10.1242/jcs.108.6.2241. View

15.

Ndaw V, Abebayehu D, Spence A, Paez P, Kolawole E, Taruselli M . TGF-β1 Suppresses IL-33-Induced Mast Cell Function. J Immunol. 2017; 199(3):866-873. PMC: 5538185. DOI: 10.4049/jimmunol.1601983. View

16.

Woolhiser M, Brockow K, Metcalfe D . Activation of human mast cells by aggregated IgG through FcgammaRI: additive effects of C3a. Clin Immunol. 2004; 110(2):172-80. DOI: 10.1016/j.clim.2003.11.007. View

17.

Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F . Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011; 128(5):989-95.e1-8. DOI: 10.1016/j.jaci.2011.07.056. View

18.

Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q . Role of transforming growth factor-β in airway remodeling in asthma. Am J Respir Cell Mol Biol. 2010; 44(2):127-33. DOI: 10.1165/rcmb.2010-0027TR. View

19.

Desai A, Jung M, Olivera A, Gilfillan A, Prussin C, Kirshenbaum A . IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3. J Allergy Clin Immunol. 2016; 137(6):1863-1871.e6. PMC: 4899186. DOI: 10.1016/j.jaci.2015.09.059. View

20.

Olsson N, Piek E, Ten Dijke P, Nilsson G . Human mast cell migration in response to members of the transforming growth factor-beta family. J Leukoc Biol. 2000; 67(3):350-6. DOI: 10.1002/jlb.67.3.350. View