Chemokine Receptor CCR2 Is Protective Toward Outer Hair Cells in Chronic Suppurative Otitis Media

Overview

Journal Immunohorizons

Specialty Allergy & Immunology

Date 2024 Sep 12

PMID 39264736

Authors

Ankur Gupta

Viktoria Schiel

Ritwija Bhattacharya

Kourosh Eftekharian

Anping Xia

Peter L Santa Maria

Affiliations

Soon will be listed here.

Abstract

Chronic suppurative otitis media (CSOM) is a neglected disease that afflicts 330 million people worldwide and is the most common cause of permanent hearing loss among children in the developing world. Previously, we discovered that outer hair cell (OHC) loss occurred in the basal turn of the cochlea and that macrophages are the major immune cells associated with OHC loss in CSOM. Macrophage-associated cytokines are upregulated. Specifically, CCL-2, an important member of the MCP family, is elevated over time following middle ear infection. CCR2 is a common receptor of the MCP family and the unique receptor of CCL2. CCR2 knockout mice (CCR2-/-) have been used extensively in studies of monocyte activation in neurodegenerative diseases. In the present study, we investigated the effect of CCR2 deletion on the cochlear immune response and OHC survival in CSOM. The OHC survival rate was 84 ± 12.5% in the basal turn of CCR2+/+ CSOM cochleae, compared with was 63 ± 19.9% in the basal turn of CCR2-/- CSOM cochleae (p ≤ 0.05). Macrophage numbers were significantly reduced in CCR2-/- CSOM cochleae compared with CCR2+/+ CSOM cochleae (p ≤ 0.001). In addition, CCL7 was upregulated, whereas IL-33 was downregulated, in CCR2-/- CSOM cochleae. Finally, the permeability of the blood-labyrinth barrier in the stria vascularis remained unchanged in CCR2-/- CSOM compared with CCR2+/+ CSOM. Taken together, the data suggest that CCR2 plays a protective role through cochlear macrophages in the CSOM cochlea.

References

Kuziel W, Morgan S, Dawson T, Griffin S, SMITHIES O, Ley K . Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci U S A. 1997; 94(22):12053-8. PMC: 23699. DOI: 10.1073/pnas.94.22.12053. View

Sautter N, Shick E, Ransohoff R, Charo I, Hirose K . CC chemokine receptor 2 is protective against noise-induced hair cell death: studies in CX3CR1(+/GFP) mice. J Assoc Res Otolaryngol. 2006; 7(4):361-72. PMC: 2504633. DOI: 10.1007/s10162-006-0051-x. View

Dostert M, Belanger C, Hancock R . Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application. J Innate Immun. 2018; 11(3):193-204. PMC: 6738209. DOI: 10.1159/000491497. View

Stamp M, Halwes M, Nisbet D, Collins D . Breaking barriers: exploring mechanisms behind opening the blood-brain barrier. Fluids Barriers CNS. 2023; 20(1):87. PMC: 10683235. DOI: 10.1186/s12987-023-00489-2. View

Ma J, Lee E, Yoon S, Min H, Oh J, Hwang I . Therapeutic effect of NLRP3 inhibition on hearing loss induced by systemic inflammation in a CAPS-associated mouse model. EBioMedicine. 2022; 82:104184. PMC: 9307460. DOI: 10.1016/j.ebiom.2022.104184. View

Korbecki J, Kojder K, Siminska D, Bohatyrewicz R, Gutowska I, Chlubek D . CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci. 2020; 21(21). PMC: 7665155. DOI: 10.3390/ijms21218412. View

Roberts T, Eugenin E, Lopez L, Romero I, Weksler B, Couraud P . CCL2 disrupts the adherens junction: implications for neuroinflammation. Lab Invest. 2012; 92(8):1213-33. PMC: 3409314. DOI: 10.1038/labinvest.2012.80. View

Sung C, Hayase N, Yuen P, Lee J, Fernandez K, Hu X . Macrophage depletion protects against cisplatin-induced ototoxicity and nephrotoxicity. Sci Adv. 2024; 10(30):eadk9878. PMC: 11268410. DOI: 10.1126/sciadv.adk9878. View

Boring L, Gosling J, Chensue S, Kunkel S, Farese Jr R, Broxmeyer H . Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J Clin Invest. 1997; 100(10):2552-61. PMC: 508456. DOI: 10.1172/JCI119798. View

10.

Siebert H, Sachse A, Kuziel W, Maeda N, Bruck W . The chemokine receptor CCR2 is involved in macrophage recruitment to the injured peripheral nervous system. J Neuroimmunol. 2000; 110(1-2):177-85. DOI: 10.1016/s0165-5728(00)00343-x. View

11.

Stamatovic S, Keep R, Kunkel S, Andjelkovic A . Potential role of MCP-1 in endothelial cell tight junction 'opening': signaling via Rho and Rho kinase. J Cell Sci. 2003; 116(Pt 22):4615-28. DOI: 10.1242/jcs.00755. View

12.

Yang W, Vethanayagam R, Dong Y, Cai Q, Hu B . Activation of the antigen presentation function of mononuclear phagocyte populations associated with the basilar membrane of the cochlea after acoustic overstimulation. Neuroscience. 2015; 303:1-15. PMC: 4532582. DOI: 10.1016/j.neuroscience.2015.05.081. View

13.

Murray C, Lopez A, Jamison D . The global burden of disease in 1990: summary results, sensitivity analysis and future directions. Bull World Health Organ. 1994; 72(3):495-509. PMC: 2486716. View

14.

Bose S, Cho J . Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases. Arch Pharm Res. 2013; 36(9):1039-50. DOI: 10.1007/s12272-013-0161-z. View

15.

Sato E, Shick H, Ransohoff R, Hirose K . Expression of fractalkine receptor CX3CR1 on cochlear macrophages influences survival of hair cells following ototoxic injury. J Assoc Res Otolaryngol. 2009; 11(2):223-34. PMC: 2862920. DOI: 10.1007/s10162-009-0198-3. View

16.

Xia A, Gao S, Yuan T, Osborn A, Bress A, Pfister M . Deficient forward transduction and enhanced reverse transduction in the alpha tectorin C1509G human hearing loss mutation. Dis Model Mech. 2010; 3(3-4):209-23. PMC: 2869304. DOI: 10.1242/dmm.004135. View

17.

Khomtchouk K, Kouhi A, Xia A, Bekale L, Massa S, Sweere J . A novel mouse model of chronic suppurative otitis media and its use in preclinical antibiotic evaluation. Sci Adv. 2020; 6(33):eabc1828. PMC: 7428333. DOI: 10.1126/sciadv.abc1828. View

18.

Rollins B . Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease. Mol Med Today. 1996; 2(5):198-204. DOI: 10.1016/1357-4310(96)88772-7. View

19.

Roblek M, Protsyuk D, Becker P, Stefanescu C, Gorzelanny C, Glaus Garzon J . CCL2 Is a Vascular Permeability Factor Inducing CCR2-Dependent Endothelial Retraction during Lung Metastasis. Mol Cancer Res. 2018; 17(3):783-793. PMC: 6445360. DOI: 10.1158/1541-7786.MCR-18-0530. View

20.

Cayrol C, Girard J . IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol. 2014; 31:31-7. DOI: 10.1016/j.coi.2014.09.004. View