Spatial Eosinophil Phenotypes as Immunopathogenic Determinants in Inflammatory Diseases
Abstract
:1. Introduction
2. Factors Governing Eosinophil Maturation, Tissue Recruitment, and Activation
3. Eosinophil Effector Functions in Diseased Tissues: Beyond Granule Protein Release
4. Heterogeneity and Fates of Eosinophils in Human Disease
5. Pharmacological Targeting of Eosinophils
6. Outstanding Questions on Eosinophil Effector Functions in Clinical Conditions
7. Novel Approaches to Decode Eosinophil Phenotypes in Diseased Human Tissues
8. Summary and Future Perspectives
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Ravin, K.A.; Loy, M. The Eosinophil in Infection. Clin. Rev. Allergy Immunol. 2016, 50, 214–227. [Google Scholar] [CrossRef]
- Gigon, L.; Fettrelet, T.; Yousefi, S.; Simon, D.; Simon, H.U. Eosinophils from A to Z. Allergy 2023, 78, 1810–1846. [Google Scholar] [CrossRef]
- Wechsler, M.E.; Munitz, A.; Ackerman, S.J.; Drake, M.G.; Jackson, D.J.; Wardlaw, A.J.; Dougan, S.K.; Berdnikovs, S.; Schleich, F.; Matucci, A.; et al. Eosinophils in Health and Disease: A State-of-the-Art Review. Mayo Clin. Proc. 2021, 96, 2694–2707. [Google Scholar] [CrossRef]
- Noble, S.L.; Mules, T.C.; Le Gros, G.; Inns, S. The immunoregulatory potential of eosinophil subsets. Immunol. Cell Biol. 2024, 102, 775–786. [Google Scholar] [CrossRef]
- Spencer, L.A.; Bonjour, K.; Melo, R.C.; Weller, P.F. Eosinophil secretion of granule-derived cytokines. Front. Immunol. 2014, 5, 496. [Google Scholar] [CrossRef]
- Bochner, B.S.; Gleich, G.J. What targeting eosinophils has taught us about their role in diseases. J. Allergy Clin. Immunol. 2010, 126, 16–25, quiz 26-17. [Google Scholar] [CrossRef]
- Weller, P.F.; Spencer, L.A. Functions of tissue-resident eosinophils. Nat. Rev. Immunol. 2017, 17, 746–760. [Google Scholar] [CrossRef]
- Akdis, C.A.; Arkwright, P.D.; Bruggen, M.C.; Busse, W.; Gadina, M.; Guttman-Yassky, E.; Kabashima, K.; Mitamura, Y.; Vian, L.; Wu, J.; et al. Type 2 immunity in the skin and lungs. Allergy 2020, 75, 1582–1605. [Google Scholar] [CrossRef]
- Hogan, S.P. Recent advances in eosinophil biology. Int. Arch. Allergy Immunol. 2007, 143 (Suppl. 1), 3–14. [Google Scholar] [CrossRef]
- Marichal, T.; Mesnil, C.; Bureau, F. Homeostatic Eosinophils: Characteristics and Functions. Front. Med. 2017, 4, 101. [Google Scholar] [CrossRef]
- Robida, P.A.; Puzzovio, P.G.; Pahima, H.; Levi-Schaffer, F.; Bochner, B.S. Human eosinophils and mast cells: Birds of a feather flock together. Immunol. Rev. 2018, 282, 151–167. [Google Scholar] [CrossRef]
- Shah, K.; Ignacio, A.; McCoy, K.D.; Harris, N.L. The emerging roles of eosinophils in mucosal homeostasis. Mucosal Immunol. 2020, 13, 574–583. [Google Scholar] [CrossRef]
- Gurtner, A.; Crepaz, D.; Arnold, I.C. Emerging functions of tissue-resident eosinophils. J. Exp. Med. 2023, 220, e20221435. [Google Scholar] [CrossRef]
- Erjefalt, J.S. Unravelling the complexity of tissue inflammation in uncontrolled and severe asthma. Curr. Opin. Pulm. Med. 2019, 25, 79–86. [Google Scholar] [CrossRef]
- Jorssen, J.; Van Hulst, G.; Mollers, K.; Pujol, J.; Petrellis, G.; Baptista, A.P.; Schetters, S.; Baron, F.; Caers, J.; Lambrecht, B.N.; et al. Single-cell proteomics and transcriptomics capture eosinophil development and identify the role of IL-5 in their lineage transit amplification. Immunity 2024, 57, 1549–1566.e8. [Google Scholar] [CrossRef]
- Willebrand, R.; Voehringer, D. Regulation of eosinophil development and survival. Curr. Opin. Hematol. 2017, 24, 9–15. [Google Scholar] [CrossRef]
- Hammad, H.; Debeuf, N.; Aegerter, H.; Brown, A.S.; Lambrecht, B.N. Emerging Paradigms in Type 2 Immunity. Annu. Rev. Immunol. 2022, 40, 443–467. [Google Scholar] [CrossRef]
- Gieseck, R.L., 3rd; Wilson, M.S.; Wynn, T.A. Type 2 immunity in tissue repair and fibrosis. Nat. Rev. Immunol. 2018, 18, 62–76. [Google Scholar] [CrossRef]
- Kopp, E.B.; Agaronyan, K.; Licona-Limon, I.; Nish, S.A.; Medzhitov, R. Modes of type 2 immune response initiation. Immunity 2023, 56, 687–694. [Google Scholar] [CrossRef]
- Hammad, H.; Lambrecht, B.N. The basic immunology of asthma. Cell 2021, 184, 1469–1485. [Google Scholar] [CrossRef]
- Ben-Baruch Morgenstern, N.; Shoda, T.; Rochman, Y.; Caldwell, J.M.; Collins, M.H.; Mukkada, V.; Putnam, P.E.; Bolton, S.M.; Felton, J.M.; Rochman, M.; et al. Local type 2 immunity in eosinophilic gastritis. J. Allergy Clin. Immunol. 2023, 152, 136–144. [Google Scholar] [CrossRef]
- O’Shea, K.M.; Aceves, S.S.; Dellon, E.S.; Gupta, S.K.; Spergel, J.M.; Furuta, G.T.; Rothenberg, M.E. Pathophysiology of Eosinophilic Esophagitis. Gastroenterology 2018, 154, 333–345. [Google Scholar] [CrossRef]
- Kolkhir, P.; Akdis, C.A.; Akdis, M.; Bachert, C.; Bieber, T.; Canonica, G.W.; Guttman-Yassky, E.; Metz, M.; Mullol, J.; Palomares, O.; et al. Type 2 chronic inflammatory diseases: Targets, therapies and unmet needs. Nat. Rev. Drug Discov. 2023, 22, 743–767. [Google Scholar] [CrossRef]
- Gause, W.C.; Rothlin, C.; Loke, P. Heterogeneity in the initiation, development and function of type 2 immunity. Nat. Rev. Immunol. 2020, 20, 603–614. [Google Scholar] [CrossRef]
- Dunn, J.L.M.; Shoda, T.; Caldwell, J.M.; Wen, T.; Aceves, S.S.; Collins, M.H.; Dellon, E.S.; Falk, G.W.; Leung, J.; Martin, L.J.; et al. Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort. J. Allergy Clin. Immunol. 2020, 145, 1629–1640.e4. [Google Scholar] [CrossRef]
- Hinks, T.S.C.; Hoyle, R.D.; Gelfand, E.W. CD8(+) Tc2 cells: Underappreciated contributors to severe asthma. Eur. Respir. Rev. 2019, 28, 190092. [Google Scholar] [CrossRef]
- Lambrecht, B.N.; Hammad, H.; Fahy, J.V. The Cytokines of Asthma. Immunity 2019, 50, 975–991. [Google Scholar] [CrossRef]
- Abdel Aziz, N.; Musaigwa, F.; Mosala, P.; Berkiks, I.; Brombacher, F. Type 2 immunity: A two-edged sword in schistosomiasis immunopathology. Trends Immunol. 2022, 43, 657–673. [Google Scholar] [CrossRef]
- Ben-Baruch Morgenstern, N.; Ballaban, A.Y.; Wen, T.; Shoda, T.; Caldwell, J.M.; Kliewer, K.; Felton, J.M.; Abonia, J.P.; Mukkada, V.A.; Putnam, P.E.; et al. Single-cell RNA sequencing of mast cells in eosinophilic esophagitis reveals heterogeneity, local proliferation, and activation that persists in remission. J. Allergy Clin. Immunol. 2022, 149, 2062–2077. [Google Scholar] [CrossRef]
- Wang, J.; Palmer, K.; Lotvall, J.; Milan, S.; Lei, X.F.; Matthaei, K.I.; Gauldie, J.; Inman, M.D.; Jordana, M.; Xing, Z. Circulating, but not local lung, IL-5 is required for the development of antigen-induced airways eosinophilia. J. Clin. Investig. 1998, 102, 1132–1141. [Google Scholar] [CrossRef]
- Esnault, S.; Johansson, M.W.; Mathur, S.K. Eosinophils, beyond IL-5. Cells 2021, 10, 2615. [Google Scholar] [CrossRef] [PubMed]
- Walsh, G.M. Eosinophil granule proteins and their role in disease. Curr. Opin. Hematol. 2001, 8, 28–33. [Google Scholar] [CrossRef] [PubMed]
- Costello, R.W.; Jacoby, D.B.; Gleich, G.J.; Fryer, A.D. Eosinophils and airway nerves in asthma. Histol. Histopathol. 2000, 15, 861–868. [Google Scholar]
- Persson, C.G.; Erjefalt, J.S. Eosinophil lysis and free granules: An in vivo paradigm for cell activation and drug development. Trends Pharmacol. Sci. 1997, 18, 117–123. [Google Scholar] [CrossRef]
- Leiferman, K.M.; Gleich, G.J. The true extent of eosinophil involvement in disease is unrecognized: The secret life of dead eosinophils. J. Leukoc. Biol. 2024, 116, 271–287. [Google Scholar] [CrossRef]
- Hirano, T.; Matsunaga, K. Measurement of Blood Eosinophils in Asthma and Chronic Obstructive Pulmonary Disease. Intern. Med. 2023, 62, 21–25. [Google Scholar] [CrossRef] [PubMed]
- Erjefalt, J.S.; Persson, C.G. New aspects of degranulation and fates of airway mucosal eosinophils. Am. J. Respir. Crit. Care Med. 2000, 161, 2074–2085. [Google Scholar] [CrossRef]
- Fettrelet, T.; Gigon, L.; Karaulov, A.; Yousefi, S.; Simon, H.U. The Enigma of Eosinophil Degranulation. Int. J. Mol. Sci. 2021, 22, 7091. [Google Scholar] [CrossRef]
- Erjefalt, J.S.; Andersson, M.; Greiff, L.; Korsgren, M.; Gizycki, M.; Jeffery, P.K.; Persson, G.A. Cytolysis and piecemeal degranulation as distinct modes of activation of airway mucosal eosinophils. J. Allergy Clin. Immunol. 1998, 102, 286–294. [Google Scholar] [CrossRef]
- Erjefalt, J.S.; Greiff, L.; Andersson, M.; Adelroth, E.; Jeffery, P.K.; Persson, C.G. Degranulation patterns of eosinophil granulocytes as determinants of eosinophil driven disease. Thorax 2001, 56, 341–344. [Google Scholar] [CrossRef]
- Melo, R.C.N.; Rothenberg, M.E. Imaging eosinophil secretory granules: From storage containers to active, immune responder organelles. J. Allergy Clin. Immunol. 2024, 155, 414–417. [Google Scholar] [CrossRef] [PubMed]
- Mukherjee, M.; Lacy, P.; Ueki, S. Eosinophil Extracellular Traps and Inflammatory Pathologies-Untangling the Web! Front. Immunol. 2018, 9, 2763. [Google Scholar] [CrossRef] [PubMed]
- Melo, R.C.N.; Silva, T.P. Eosinophil activation during immune responses: An ultrastructural view with an emphasis on viral diseases. J. Leukoc. Biol. 2024, 116, 321–334. [Google Scholar] [CrossRef] [PubMed]
- Weihrauch, T.; Melo, R.C.N.; Gray, N.; Voehringer, D.; Weller, P.F.; Raap, U. Eosinophil extracellular vesicles and DNA traps in allergic inflammation. Front. Allergy 2024, 5, 1448007. [Google Scholar] [CrossRef]
- Ueki, S.; Miyabe, Y.; Yamamoto, Y.; Fukuchi, M.; Hirokawa, M.; Spencer, L.A.; Weller, P.F. Charcot-Leyden Crystals in Eosinophilic Inflammation: Active Cytolysis Leads to Crystal Formation. Curr. Allergy Asthma Rep. 2019, 19, 35. [Google Scholar] [CrossRef]
- Neves, J.S.; Perez, S.A.; Spencer, L.A.; Melo, R.C.; Reynolds, L.; Ghiran, I.; Mahmudi-Azer, S.; Odemuyiwa, S.O.; Dvorak, A.M.; Moqbel, R.; et al. Eosinophil granules function extracellularly as receptor-mediated secretory organelles. Proc. Natl. Acad. Sci. USA 2008, 105, 18478–18483. [Google Scholar] [CrossRef]
- Carmo, L.A.S.; Bonjour, K.; Spencer, L.A.; Weller, P.F.; Melo, R.C.N. Single-Cell Analyses of Human Eosinophils at High Resolution to Understand Compartmentalization and Vesicular Trafficking of Interferon-Gamma. Front. Immunol. 2018, 9, 1542. [Google Scholar] [CrossRef]
- Arnold, I.C.; Munitz, A. Spatial adaptation of eosinophils and their emerging roles in homeostasis, infection and disease. Nat. Rev. Immunol. 2024, 24, 858–877. [Google Scholar] [CrossRef]
- Lacy, P.; Moqbel, R. Eosinophil cytokines. Chem. Immunol. 2000, 76, 134–155. [Google Scholar]
- Grisaru-Tal, S.; Munitz, A. T cell-eosinophil crosstalk-A new road for effective immune checkpoint blockade in breast cancer? Cancer Cell 2023, 41, 9–11. [Google Scholar] [CrossRef]
- LeSuer, W.E.; Kienzl, M.; Ochkur, S.I.; Schicho, R.; Doyle, A.D.; Wright, B.L.; Rank, M.A.; Krupnick, A.S.; Kita, H.; Jacobsen, E.A. Eosinophils promote effector functions of lung group 2 innate lymphoid cells in allergic airway inflammation in mice. J. Allergy Clin. Immunol. 2023, 152, 469–485.e10. [Google Scholar] [CrossRef] [PubMed]
- Bal, S.M.; Bernink, J.H.; Nagasawa, M.; Groot, J.; Shikhagaie, M.M.; Golebski, K.; van Drunen, C.M.; Lutter, R.; Jonkers, R.E.; Hombrink, P.; et al. IL-1beta, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat. Immunol. 2016, 17, 636–645. [Google Scholar] [CrossRef] [PubMed]
- Chu, D.K.; Jimenez-Saiz, R.; Verschoor, C.P.; Walker, T.D.; Goncharova, S.; Llop-Guevara, A.; Shen, P.; Gordon, M.E.; Barra, N.G.; Bassett, J.D.; et al. Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo. J. Exp. Med. 2014, 211, 1657–1672. [Google Scholar] [CrossRef]
- Jacobsen, E.A.; Zellner, K.R.; Colbert, D.; Lee, N.A.; Lee, J.J. Eosinophils regulate dendritic cells and Th2 pulmonary immune responses following allergen provocation. J. Immunol. 2011, 187, 6059–6068. [Google Scholar] [CrossRef]
- Kanda, A.; Yun, Y.; Bui, D.V.; Nguyen, L.M.; Kobayashi, Y.; Suzuki, K.; Mitani, A.; Sawada, S.; Hamada, S.; Asako, M.; et al. The multiple functions and subpopulations of eosinophils in tissues under steady-state and pathological conditions. Allergol. Int. 2021, 70, 9–18. [Google Scholar] [CrossRef]
- Mesnil, C.; Raulier, S.; Paulissen, G.; Xiao, X.; Birrell, M.A.; Pirottin, D.; Janss, T.; Starkl, P.; Ramery, E.; Henket, M.; et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Investig. 2016, 126, 3279–3295. [Google Scholar] [CrossRef]
- Gurtner, A.; Borrelli, C.; Gonzalez-Perez, I.; Bach, K.; Acar, I.E.; Nunez, N.G.; Crepaz, D.; Handler, K.; Vu, V.P.; Lafzi, A.; et al. Active eosinophils regulate host defence and immune responses in colitis. Nature 2023, 615, 151–157. [Google Scholar] [CrossRef] [PubMed]
- Rodrigo-Munoz, J.M.; Naharro-Gonzalez, S.; Callejas, S.; Relano-Ruperez, C.; Torroja, C.; Benguria, A.; Lorente-Sorolla, C.; Gil-Martinez, M.; Garcia de Castro, Z.; Canas, J.A.; et al. Single-cell RNA sequencing of human blood eosinophils reveals plasticity and absence of canonical cell subsets. Allergy 2025, 80, 570–574. [Google Scholar] [CrossRef]
- Iwasaki, N.; Poposki, J.A.; Oka, A.; Kidoguchi, M.; Klingler, A.I.; Suh, L.A.; Bai, J.; Stevens, W.W.; Peters, A.T.; Grammer, L.C.; et al. Single cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue. J. Allergy Clin. Immunol. 2024, 154, 952–964. [Google Scholar] [CrossRef]
- Ding, J.; Garber, J.J.; Uchida, A.; Lefkovith, A.; Carter, G.T.; Vimalathas, P.; Canha, L.; Dougan, M.; Staller, K.; Yarze, J.; et al. An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission. Nat. Commun. 2024, 15, 3344. [Google Scholar] [CrossRef]
- Jogdand, P.; Siddhuraj, P.; Mori, M.; Sanden, C.; Jonsson, J.; Walls, A.F.; Kearley, J.; Humbles, A.A.; Kolbeck, R.; Bjermer, L.; et al. Eosinophils, Basophils, and Type 2 Immune Microenvironments in COPD-Affected Lung Tissue. Eur. Respir. J. 2020, 55, 1900110. [Google Scholar] [CrossRef]
- Kearley, J.; Silver, J.S.; Sanden, C.; Liu, Z.; Berlin, A.A.; White, N.; Mori, M.; Pham, T.H.; Ward, C.K.; Criner, G.J.; et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity 2015, 42, 566–579. [Google Scholar] [CrossRef] [PubMed]
- Erjefalt, J.S. Anatomical and histopathological approaches to asthma phenotyping. Respir. Med. 2023, 210, 107168. [Google Scholar] [CrossRef] [PubMed]
- Kraft, M.; Pak, J.; Martin, R.J.; Kaminsky, D.; Irvin, C.G. Distal lung dysfunction at night in nocturnal asthma. Am. J. Respir. Crit. Care Med. 2001, 163, 1551–1556. [Google Scholar] [CrossRef] [PubMed]
- Bergqvist, A.; Andersson, C.K.; Mori, M.; Walls, A.F.; Bjermer, L.; Erjefalt, J.S. Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control. Clin. Sci. 2015, 128, 47–56. [Google Scholar] [CrossRef]
- Hopp, R.J.; Wilson, M.C.; Pasha, M.A. Small Airway Disease in Pediatric Asthma: The Who, What, When, Where, Why, and How to Remediate. A Review and Commentary. Clin. Rev. Allergy Immunol. 2022, 62, 145–159. [Google Scholar] [CrossRef]
- Trejo Bittar, H.E.; Doberer, D.; Mehrad, M.; Strollo, D.C.; Leader, J.K.; Wenzel, S.; Yousem, S.A. Histologic Findings of Severe/Therapy-Resistant Asthma From Video-assisted Thoracoscopic Surgery Biopsies. Am. J. Surg. Pathol. 2017, 41, 182–188. [Google Scholar] [CrossRef]
- Wang, H.B.; Akuthota, P.; Kanaoka, Y.; Weller, P.F. Airway eosinophil migration into lymph nodes in mice depends on leukotriene C(4). Allergy 2017, 72, 927–936. [Google Scholar] [CrossRef]
- Shi, H.Z.; Humbles, A.; Gerard, C.; Jin, Z.; Weller, P.F. Lymph node trafficking and antigen presentation by endobronchial eosinophils. J. Clin. Investig. 2000, 105, 945–953. [Google Scholar] [CrossRef]
- Cagnoni, E.F.; Ferreira, D.S.; Ferraz da Silva, L.F.; Nicoletti Carvalho Petry, A.L.; Gomes dos Santos, A.B.; Rodrigues Medeiros, M.C.; Dolhnikoff, M.; Rabe, K.F.; Mauad, T. Bronchopulmonary lymph nodes and large airway cell trafficking in patients with fatal asthma. J. Allergy Clin. Immunol. 2015, 135, 1352–1357.e9. [Google Scholar] [CrossRef]
- Tamura, N.; Ishii, N.; Nakazawa, M.; Nagoya, M.; Yoshinari, M.; Amano, T.; Nakazima, H.; Minami, M. Requirement of CD80 and CD86 molecules for antigen presentation by eosinophils. Scand J. Immunol. 1996, 44, 229–238. [Google Scholar] [CrossRef] [PubMed]
- Akuthota, P.; Ueki, S.; Estanislau, J.; Weller, P.F. Human eosinophils express functional CCR7. Am. J. Respir. Cell Mol. Biol. 2013, 48, 758–764. [Google Scholar] [CrossRef]
- Erjefalt, J.S.; Uller, L.; Malm-Erjefalt, M.; Persson, C.G. Rapid and efficient clearance of airway tissue granulocytes through transepithelial migration. Thorax 2004, 59, 136–143. [Google Scholar] [CrossRef]
- Uller, L.; Persson, C.G.; Erjefalt, J.S. Resolution of airway disease: Removal of inflammatory cells through apoptosis, egression or both? Trends Pharmacol. Sci. 2006, 27, 461–466. [Google Scholar] [CrossRef]
- Uller, L.; Persson, C.G.; Kallstrom, L.; Erjefalt, J.S. Lung tissue eosinophils may be cleared through luminal entry rather than apoptosis: Effects of steroid treatment. Am. J. Respir. Crit. Care Med. 2001, 164, 1948–1956. [Google Scholar] [CrossRef] [PubMed]
- Haruna, N.F.; Berdnikovs, S.; Nie, Z. Eosinophil biology from the standpoint of metabolism: Implications for metabolic disorders and asthma. J. Leukoc. Biol. 2024, 116, 288–296. [Google Scholar] [CrossRef] [PubMed]
- Andersson, C.K.; Bergqvist, A.; Mori, M.; Mauad, T.; Bjermer, L.; Erjefalt, J.S. Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma. J. Allergy Clin. Immunol. 2011, 127, 905–912.e7. [Google Scholar] [CrossRef]
- Porsbjerg, C.; Melen, E.; Lehtimaki, L.; Shaw, D. Asthma. Lancet 2023, 401, 858–873. [Google Scholar] [CrossRef]
- Peters, M.C.; Wenzel, S.E. Intersection of biology and therapeutics: Type 2 targeted therapeutics for adult asthma. Lancet 2020, 395, 371–383. [Google Scholar] [CrossRef]
- Moran, A.M.; Ramakrishnan, S.; Borg, C.A.; Connolly, C.M.; Couillard, S.; Mwasuku, C.M.; Pavord, I.D.; Hinks, T.S.C.; Lehtimaki, L. Blood Eosinophil Depletion with Mepolizumab, Benralizumab and Prednisolone in Eosinophilic Asthma. Am. J. Respir. Crit. Care Med. 2020, 202, 1314–1316. [Google Scholar] [CrossRef]
- Sim, S.; Choi, Y.; Park, H.S. Immunologic Basis of Type 2 Biologics for Severe Asthma. Immune Netw. 2022, 22, e45. [Google Scholar] [CrossRef] [PubMed]
- Matucci, A.; Maggi, E.; Vultaggio, A. Eosinophils, the IL-5/IL-5Ralpha axis, and the biologic effects of benralizumab in severe asthma. Respir. Med. 2019, 160, 105819. [Google Scholar] [CrossRef]
- Dellon, E.S.; Peterson, K.A.; Murray, J.A.; Falk, G.W.; Gonsalves, N.; Chehade, M.; Genta, R.M.; Leung, J.; Khoury, P.; Klion, A.D.; et al. Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis. N. Engl. J. Med. 2020, 383, 1624–1634. [Google Scholar] [CrossRef]
- Pavord, I.D.; Holliday, M.; Reddel, H.K.; Braithwaite, I.; Ebmeier, S.; Hancox, R.J.; Harrison, T.; Houghton, C.; Oldfield, K.; Papi, A.; et al. Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: A prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial. Lancet Respir. Med. 2020, 8, 671–680. [Google Scholar] [CrossRef] [PubMed]
- Custovic, A.; Siddiqui, S.; Saglani, S. Considering biomarkers in asthma disease severity. J. Allergy Clin. Immunol. 2022, 149, 480–487. [Google Scholar] [CrossRef]
- Malm-Erjefalt, M.; Greiff, L.; Ankerst, J.; Andersson, M.; Wallengren, J.; Cardell, L.O.; Rak, S.; Persson, C.G.; Erjefalt, J.S. Circulating eosinophils in asthma, allergic rhinitis, and atopic dermatitis lack morphological signs of degranulation. Clin. Exp. Allergy 2005, 35, 1334–1340. [Google Scholar] [CrossRef]
- Metcalfe, D.D.; Pawankar, R.; Ackerman, S.J.; Akin, C.; Clayton, F.; Falcone, F.H.; Gleich, G.J.; Irani, A.M.; Johansson, M.W.; Klion, A.D.; et al. Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases. World Allergy Organ. J. 2016, 9, 7. [Google Scholar] [CrossRef] [PubMed]
- Schoepfer, A.M.; Safroneeva, E. Pharmacologic Treatment of Eosinophilic Esophagitis: Efficacious, Likely Efficacious, and Failed Drugs. Inflamm. Intest. Dis. 2024, 9, 199–209. [Google Scholar] [CrossRef]
- Rothenberg, M.E.; Dellon, E.S.; Collins, M.H.; Bredenoord, A.J.; Hirano, I.; Peterson, K.A.; Brooks, L.; Caldwell, J.M.; Fjallbrant, H.; Grindebacke, H.; et al. Eosinophil Depletion with Benralizumab for Eosinophilic Esophagitis. N. Engl. J. Med. 2024, 390, 2252–2263. [Google Scholar] [CrossRef]
- Watanabe, H.; Shirai, T.; Hirai, K.; Akamatsu, T.; Nakayasu, H.; Tamura, K.; Masuda, T.; Takahashi, S.; Tanaka, Y.; Kishimoto, Y.; et al. Blood eosinophil count and FeNO to predict benralizumab effectiveness in real-life severe asthma patients. J. Asthma. 2022, 59, 1796–1804. [Google Scholar] [CrossRef]
- Katz, L.E.; Gleich, G.J.; Hartley, B.F.; Yancey, S.W.; Ortega, H.G. Blood eosinophil count is a useful biomarker to identify patients with severe eosinophilic asthma. Ann. Am. Thorac. Soc. 2014, 11, 531–536. [Google Scholar] [CrossRef] [PubMed]
- Ortega, H.G.; Yancey, S.W.; Mayer, B.; Gunsoy, N.B.; Keene, O.N.; Bleecker, E.R.; Brightling, C.E.; Pavord, I.D. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: A secondary analysis of the DREAM and MENSA studies. Lancet Respir. Med. 2016, 4, 549–556. [Google Scholar] [CrossRef] [PubMed]
- Rojo-Tolosa, S.; Sanchez-Martinez, J.A.; Caballero-Vazquez, A.; Pineda-Lancheros, L.E.; Gonzalez-Gutierrez, M.V.; Perez-Ramirez, C.; Jimenez-Morales, A.; Morales-Garcia, C. SingleNucleotide Polymorphisms as Biomarkers of Mepolizumab and Benralizumab Treatment Response in Severe Eosinophilic Asthma. Int. J. Mol. Sci. 2024, 25, 8139. [Google Scholar] [CrossRef]
- Rosenberg, H.F.; Dyer, K.D.; Foster, P.S. Eosinophils: Changing perspectives in health and disease. Nat. Rev. Immunol. 2013, 13, 9–22. [Google Scholar] [CrossRef] [PubMed]
- Nair, P.; Pizzichini, M.M.; Kjarsgaard, M.; Inman, M.D.; Efthimiadis, A.; Pizzichini, E.; Hargreave, F.E.; O’Byrne, P.M. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 2009, 360, 985–993. [Google Scholar] [CrossRef]
- Venegas Garrido, C.; Mukherjee, M.; Svenningsen, S.; Nair, P. Eosinophil-mucus interplay in severe asthma: Implications for treatment with biologicals. Allergol. Int. 2024, 73, 351–361. [Google Scholar] [CrossRef]
- Tang, M.; Charbit, A.R.; Johansson, M.W.; Jarjour, N.N.; Denlinger, L.C.; Raymond, W.W.; Peters, M.C.; Dunican, E.M.; Castro, M.; Sumino, K.; et al. Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma. J. Allergy Clin. Immunol. 2024, 154, 580–591.e6. [Google Scholar] [CrossRef]
- Barretto, K.T.; Brockman-Schneider, R.A.; Kuipers, I.; Basnet, S.; Bochkov, Y.A.; Altman, M.C.; Jarjour, N.N.; Gern, J.E.; Esnault, S. Human airway epithelial cells express a functional IL-5 receptor. Allergy 2020, 75, 2127–2130. [Google Scholar] [CrossRef]
- Bajbouj, K.; AbuJabal, R.; Sahnoon, L.; Olivenstein, R.; Mahboub, B.; Hamid, Q. IL-5 receptor expression in lung fibroblasts: Potential role in airway remodeling in asthma. Allergy 2023, 78, 882–885. [Google Scholar] [CrossRef]
- Troch, K.F.; Jakob, M.O.; Forster, P.M.; Jarick, K.J.; Schreiber, J.; Preusser, A.; Guerra, G.M.; Durek, P.; Tizian, C.; Sterczyk, N.; et al. Group 2 innate lymphoid cells are a non-redundant source of interleukin-5 required for development and function of murine B1 cells. Nat. Commun. 2024, 15, 10566. [Google Scholar] [CrossRef]
- van Rensburg, I.C.; Wagman, C.; Stanley, K.; Beltran, C.; Ronacher, K.; Walzl, G.; Loxton, A.G. Successful TB treatment induces B-cells expressing FASL and IL5RA mRNA. Oncotarget 2017, 8, 2037–2043. [Google Scholar] [CrossRef] [PubMed]
- O’Sullivan, J.A.; Youngblood, B.A.; Schleimer, R.P.; Bochner, B.S. Siglecs as potential targets of therapy in human mast cell- and/or eosinophil-associated diseases. Semin. Immunol. 2023, 69, 101799. [Google Scholar] [CrossRef] [PubMed]
- Johansson, M.W.; Kelly, E.A.; Nguyen, C.L.; Jarjour, N.N.; Bochner, B.S. Characterization of Siglec-8 Expression on Lavage Cells after Segmental Lung Allergen Challenge. Int. Arch. Allergy Immunol. 2018, 177, 16–28. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.Y.; Jeong, D.; Kim, J.H.; Chung, D.H. Innate Type-2 Cytokines: From Immune Regulation to Therapeutic Targets. Immune Netw. 2024, 24, e6. [Google Scholar] [CrossRef]
- Wechsler, M.E.; Ruddy, M.K.; Pavord, I.D.; Israel, E.; Rabe, K.F.; Ford, L.B.; Maspero, J.F.; Abdulai, R.M.; Hu, C.C.; Martincova, R.; et al. Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma. N. Engl. J. Med. 2021, 385, 1656–1668. [Google Scholar] [CrossRef]
- Rabe, K.F.; Martinez, F.J.; Bhatt, S.P.; Kawayama, T.; Cosio, B.G.; Mroz, R.M.; Boomsma, M.M.; Goulaouic, H.; Nivens, M.C.; Djandji, M.; et al. AERIFY-1/2: Two phase 3, randomised, controlled trials of itepekimab in former smokers with moderate-to-severe COPD. ERJ Open Res. 2024, 10, 718–2023. [Google Scholar] [CrossRef]
- England, E.; Rees, D.G.; Scott, I.C.; Carmen, S.; Chan, D.T.Y.; Chaillan Huntington, C.E.; Houslay, K.F.; Erngren, T.; Penney, M.; Majithiya, J.B.; et al. Tozorakimab (MEDI3506): An anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction. Sci. Rep. 2023, 13, 9825. [Google Scholar] [CrossRef]
- Yousuf, A.J.; Mohammed, S.; Carr, L.; Yavari Ramsheh, M.; Micieli, C.; Mistry, V.; Haldar, K.; Wright, A.; Novotny, P.; Parker, S.; et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): A phase 2a, placebo-controlled trial. Lancet Respir. Med. 2022, 10, 469–477. [Google Scholar] [CrossRef]
- Siddiqui, S.; Wenzel, S.E.; Bozik, M.E.; Archibald, D.G.; Dworetzky, S.I.; Mather, J.L.; Killingsworth, R.; Ghearing, N.; Schwartz, J.T.; Ochkur, S.I.; et al. Safety and Efficacy of Dexpramipexole in Eosinophilic Asthma (EXHALE): A randomized controlled trial. J. Allergy Clin. Immunol. 2023, 152, 1121–1130.e10. [Google Scholar] [CrossRef]
- Burrows, K.; Ngai, L.; Chiaranunt, P.; Watt, J.; Popple, S.; Forde, B.; Denha, S.; Olyntho, V.M.; Tai, S.L.; Cao, E.Y.; et al. A gut commensal protozoan determines respiratory disease outcomes by shaping pulmonary immunity. Cell 2025, 188, 316–330.e312. [Google Scholar] [CrossRef]
- Li, X.; Hawkins, G.A.; Moore, W.C.; Hastie, A.T.; Ampleford, E.J.; Milosevic, J.; Li, H.; Busse, W.W.; Erzurum, S.C.; Kaminski, N.; et al. Expression of asthma susceptibility genes in bronchial epithelial cells and bronchial alveolar lavage in the Severe Asthma Research Program (SARP) cohort. J. Asthma 2016, 53, 775–782. [Google Scholar] [CrossRef] [PubMed]
- Fahy, J.V.; Jackson, N.D.; Sajuthi, S.P.; Pruesse, E.; Moore, C.M.; Everman, J.L.; Rios, C.; Tang, M.; Gauthier, M.; Wenzel, S.E.; et al. Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma. Am. J. Respir. Crit. Care Med. 2025, 211, 194–204. [Google Scholar] [CrossRef] [PubMed]
- Porsbjerg, C.; Maitland-van der Zee, A.H.; Brusselle, G.; Canonica, G.W.; Agusti, A.; Faner, R.; Vogelmeier, C.F.; Nawijn, M.; van den Berge, M.; Rusconi, F.; et al. 3TR: A pan-European cross-disease research consortium aimed at improving personalised biological treatment of asthma and COPD. Eur. Respir. J. 2021, 58, 2102168. [Google Scholar] [CrossRef] [PubMed]
- Zein, J.G.; Zounemat-Kerman, N.; Adcock, I.M.; Hu, B.; Attaway, A.; Castro, M.; Dahlen, S.E.; Denlinger, L.C.; Erzurum, S.C.; Fahy, J.V.; et al. Development of an asthma health-care burden score as a measure of severity and predictor of remission in SARP III and U-BIOPRED: Results from two major longitudinal asthma cohorts. Lancet Respir. Med. 2025, 13, 35–46. [Google Scholar] [CrossRef]
- Wright, B.L.; Abonia, J.P.; Abud, E.M.; Aceves, S.S.; Ackerman, S.J.; Braskett, M.; Chang, J.W.; Chehade, M.; Constantine, G.M.; Davis, C.M.; et al. Advances and ongoing challenges in eosinophilic gastrointestinal disorders presented at the CEGIR/TIGERs Symposium at the 2024 American Academy of Allergy, Asthma & Immunology meeting. J. Allergy Clin. Immunol. 2024, 154, 882–892. [Google Scholar]
- Malm-Erjefalt, M.; Stevens, T.R.; Persson, C.G.; Erjefalt, J.S. Discontinuous Percoll gradient centrifugation combined with immunomagnetic separation obviates the need for erythrocyte lysis and yields isolated eosinophils with minimal granule abnormalities. J. Immunol. Methods 2004, 288, 99–109. [Google Scholar] [CrossRef]
- Khoury, P.; Akuthota, P.; Ackerman, S.J.; Arron, J.R.; Bochner, B.S.; Collins, M.H.; Kahn, J.E.; Fulkerson, P.C.; Gleich, G.J.; Gopal-Srivastava, R.; et al. Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J. Leukoc. Biol. 2018, 104, 69–83. [Google Scholar] [CrossRef]
- Jacobsen, E.A.; Jackson, D.J.; Heffler, E.; Mathur, S.K.; Bredenoord, A.J.; Pavord, I.D.; Akuthota, P.; Roufosse, F.; Rothenberg, M.E. Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies. Annu. Rev. Immunol. 2021, 39, 719–757. [Google Scholar] [CrossRef]
- Borrelli, C.; Gurtner, A.; Arnold, I.C.; Moor, A.E. Stress-free single-cell transcriptomic profiling and functional genomics of murine eosinophils. Nat. Protoc. 2024, 19, 1679–1709. [Google Scholar] [CrossRef]
- Bell, A.T.F.; Mitchell, J.T.; Kiemen, A.L.; Lyman, M.; Fujikura, K.; Lee, J.W.; Coyne, E.; Shin, S.M.; Nagaraj, S.; Deshpande, A.; et al. PanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration. Cell Syst. 2024, 15, 753–769.e5. [Google Scholar] [CrossRef]
- Smith, K.D.; Prince, D.K.; MacDonald, J.W.; Bammler, T.K.; Akilesh, S. Challenges and Opportunities for the Clinical Translation of Spatial Transcriptomics Technologies. Glomerular Dis. 2024, 4, 49–63. [Google Scholar] [CrossRef] [PubMed]
- Huang, C.H.; Lichtarge, S.; Fernandez, D. Integrative whole slide image and spatial transcriptomics analysis with QuST and QuPath. npj Precis. Oncol. 2025, 9, 70. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Erjefält, J.S. Spatial Eosinophil Phenotypes as Immunopathogenic Determinants in Inflammatory Diseases. Cells 2025, 14, 847. https://doi.org/10.3390/cells14110847
Erjefält JS. Spatial Eosinophil Phenotypes as Immunopathogenic Determinants in Inflammatory Diseases. Cells. 2025; 14(11):847. https://doi.org/10.3390/cells14110847
Chicago/Turabian StyleErjefält, Jonas S. 2025. "Spatial Eosinophil Phenotypes as Immunopathogenic Determinants in Inflammatory Diseases" Cells 14, no. 11: 847. https://doi.org/10.3390/cells14110847
APA StyleErjefält, J. S. (2025). Spatial Eosinophil Phenotypes as Immunopathogenic Determinants in Inflammatory Diseases. Cells, 14(11), 847. https://doi.org/10.3390/cells14110847