The role of macrophages in chronic rhinosinusitis with nasal polyps

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by dysbiosis of nasal microbiota and dysregulation of the immune system. Macrophages are essential for protecting against infections, but their roles and mechanisms in CRSwNP are not fully understood. To date, we gradually recognize the heterogeneity of macrophages, and new subsets of macrophages have been identified at transcriptional level due to the development of single cell RNA-sequencing. In this review, we summarize the generation, polarization, phenotype identification, and function of macrophages in CRSwNP, providing a comprehensive understanding of macrophages in CRSwNP. Additionally, we also explore how macrophages interact with other cells, including epithelial cells, immune cells, and neurons, which can worsen inflammation. A better understanding of the role of macrophages could improve their ability to clear bacteria and reduce chronic inflammation in CRSwNP, which might be clinically beneficial for CRSwNP patients.

Keywords

chronic rhinosinusitis with nasal polyps / generation / macrophages / polarization / Staphylococcus aureus

References

[1] Tomassen P , Vandeplas G , Van Zele T , et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016; 137 (5): 1449- 1456.e4.

[2] Karin J , Tim D , Gabriele H , Cardell L , Marit W , Claus B . Type 2 inflammatory shift in chronic rhinosinusitis during 2007-2018 in Belgium. Laryngoscope. 2021; 131 (5): E1408- E1414.

[3] Teufelberger AR , Nordengrün M , Braun H , et al. The IL-33/ST2 axis is crucial in type 2 airway responses induced by Staphylococcus aureus-derived serine protease-like protein D. J Allergy Clin Immunol. 2018; 141 (2): 549- 559.e7.

[4] Vickery TW , Ramakrishnan VR , Suh JD . The role of Staphylococcus aureus in patients with chronic sinusitis and nasal polyposis. Curr Allergy Asthma Rep. 2019; 19 (4): 21.

[5] Krysko O , Holtappels G , Zhang N , et al. Alternatively activated macrophages and impaired phagocytosis of S. aureus in chronic rhinosinusitis. Allergy. 2011; 66 (3): 396- 403.

[6] Pidwill GR , Gibson JF , Cole J , Renshaw SA , Foster SJ . The role of macrophages in Staphylococcus aureus infection. Front Immunol. 2020; 11: 620339.

[7] Bao X , Liu B , Jiang Y , et al. Loss of SENP3 mediated the formation of nasal polyps in nasal mucosal inflammation by increasing alternative activated macrophage. Immun Inflamm Dis. 2023; 11 (2): e781.

[8] Xie S , Tong Z , Zhang J , et al. Elevated MIF identified by multiple cytokine analyses facilitates macrophage M2 polarization contributing to postoperative recurrence in chronic rhinosinusitis with nasal polyps. Rhinology. 2024; 62 (4): 432- 445.

[9] Wang W , Xu Y , Wang L , et al. Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis. Nat Immunol. 2022; 23 (10): 1484- 1494.

[10] Yona S , Kim KW , Wolf Y , et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013; 38 (1): 79- 91.

[11] Wang Z , Wu Z , Wang H , et al. An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development. Cell. 2023; 186 (20): 4454- 4471.e19.

[12] Gomez Perdiguero E , Klapproth K , Schulz C , et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015; 518 (7540): 547- 551.

[13] Guilliams M , De Kleer I , Henri S , et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med. 2013; 210 (10): 1977- 1992.

[14] Bian Z , Gong Y , Huang T , et al. Deciphering human macrophage development at single-cell resolution. Nature. 2020; 582 (7813): 571- 576.

[15] Mass E , Ballesteros I , Farlik M , et al. Specification of tissue-resident macrophages during organogenesis. Science. 2016; 353 (6304): aaf4238.

[16] Evren E , Ringqvist E , Doisne JM , et al. CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages. J Exp Med. 2022; 219 (2): e20210987.

[17] Lazarov T , Juarez-Carreño S , Cox N , Geissmann F . Physiology and diseases of tissue-resident macrophages. Nature. 2023; 618 (7966): 698- 707.

[18] Liu Z , Gu Y , Chakarov S , et al. Fate mapping via Ms4a3-expression history traces monocyte-derived cells. Cell. 2019; 178 (6): 1509- 1525.e19.

[19] Eguíluz-Gracia I , Bosco A , Dollner R , et al. Rapid recruitment of CD14(+) monocytes in experimentally induced allergic rhinitis in human subjects. J Allergy Clin Immunol. 2016; 137 (6): 1872- 1881.e12.

[20] Kolahian S , Öz HH , Zhou B , et al. The emerging role of myeloidderived suppressor cells in lung diseases. Eur Respir J. 2016; 47 (3): 967- 977.

[21] Lavrich KS , Speen AM , Ghio AJ , Bromberg PA , Samet JM , Alexis NE . Macrophages from the upper and lower human respiratory tract are metabolically distinct. Am J Physiol Lung Cell Mol Physiol. 2018; 315 (5): L752- l764.

[22] Zhong B , Du J , Liu F , et al. Hypoxia-induced factor-1α induces NLRP3 expression by M1 macrophages in noneosinophilic chronic rhinosinusitis with nasal polyps. Allergy. 2021; 76 (2): 582- 586.

[23] Zhong B , Du J , Liu F , et al. Activation of the mTOR/HIF-1α/VEGF axis promotes M1 macrophage polarization in non-eosinophilic chronic rhinosinusitis with nasal polyps. Allergy. 2022; 77 (2): 643- 646.

[24] Wang ZC , Yao Y , Wang N , et al. Deficiency in interleukin-10 production by M2 macrophages in eosinophilic chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2018; 8 (11): 1323- 1333.

[25] Kim RJ , Yin T , Chen CJ , et al. The interaction between bacteria and mucosal immunity in chronic rhinosinusitis: a prospective crosssectional analysis. Am J Rhinol. 2013; 27 (6): e183- e189.

[26] Wang E , Hao Y , Song J , et al. M2 macrophage derived HMOX1 defines chronic rhinosinusitis with nasal polyps. Clin Transl Allergy. 2024; 14 (12): e70014.

[27] Yao Y , Wang ZC , Liu JX , et al. Increased expression of TIPE2 in alternatively activated macrophages is associated with eosinophilic inflammation and disease severity in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2017; 7 (10): 963- 972.

[28] Wang T , Chen Y , Gao R , Shui J , Xie B . Overexpression of AXL on macrophages associates with disease severity and recurrence in chronic rhinosinusitis with nasal polyps. Int Immunopharmacol. 2023; 121: 110449.

[29] Xuan L , Zhang N , Wang X , Bachert C . IL-10 family cytokines in chronic rhinosinusitis with nasal polyps: from experiments to the clinic. Front Immunol. 2022; 13: 947983.

[30] Haimerl P , Bernhardt U , Schindela S , et al. Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. J Allergy Clin Immunol. 2021; 147 (2): 587- 599.

[31] Liu C , Wang K , Liu W , Zhang J , Fan Y , Sun Y . ALOX15(+) M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2024; 154: 592- 608.

[32] Nakayama T , Lee IT , Le W , et al. Inflammatory molecular endotypes of nasal polyps derived from White and Japanese populations. J Allergy Clin Immunol. 2022; 149 (4): 1296- 1308.e6.

[33] Chalermwatanachai T , Vilchez-Vargas R , Holtappels G , et al. Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota. Sci Rep. 2018; 8 (1): 7926.

[34] Zhao Y , Chen J , Hao Y , et al. Predicting the recurrence of chronic rhinosinusitis with nasal polyps using nasal microbiota. Allergy. 2022; 77 (2): 540- 549.

[35] Lan F , Zhang N , Holtappels G , et al. Staphylococcus aureus induces a mucosal type 2 immune response via epithelial cell-derived cytokines. Am J Respir Crit Care Med. 2018; 198 (4): 452- 463.

[36] Bachert C , Humbert M , Hanania NA , et al. Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge. Eur Respir J. 2020; 55 (4): 1901592.

[37] Askarian F , Wagner T , Johannessen M , Nizet V . Staphylococcus aureus modulation of innate immune responses through Toll-like (TLR), (NOD)-like (NLR) and C-type lectin (CLR) receptors. FEMS Microbiol Rev. 2018; 42 (5): 656- 671.

[38] Levin R , Grinstein S , Canton J . The life cycle of phagosomes: formation, maturation, and resolution. Immunol Rev. 2016; 273 (1): 156- 179.

[39] Ghosh R , Bishayi B . Endogenous blocking of TLR2 along with TNF-α and IL-1β ameliorates the severity of the S. aureus arthritis via modulating STAT3/SOCS3 expressions in tissue resident macrophages. Microb Pathog. 2024; 187: 106518.

[40] Jubrail J , Morris P , Bewley MA , et al. Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages. Cell Microbiol. 2016; 18 (1): 80- 96.

[41] Lan F , Zhong H , Zhang N , et al. IFN-lambda1 enhances Staphylococcus aureus clearance in healthy nasal mucosa but not in nasal polyps. J Allergy Clin Immunol. 2019; 143 (4): 1416- 1425.e4.

[42] Tang XZ , Kreuk LSM , Cho C , Metzger RJ , Allen CDC . Bronchusassociated macrophages efficiently capture and present soluble inhaled antigens and are capable of local Th2 cell activation. eLife. 2022; 11: e63296.

[43] Choi GE , Yoon SY , Kim JY , Kang DY , Jang YJ , Kim HS . Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis. J Allergy Clin Immunol. 2018; 141 (3): 938- 950.e12.

[44] Murray PJ , Wynn TA . Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011; 11 (11): 723- 737.

[45] Scott CL , Guilliams M . Tissue unit-ed: lung cells team up to drive alveolar macrophage development. Cell. 2018; 175 (4): 898- 900.

[46] Yan B , Lan F , Li J , Wang C , Zhang L . The mucosal concept in chronic rhinosinusitis: focus on the epithelial barrier. J Allergy Clin Immunol. 2024; 153 (5): 1206- 1214.

[47] Skronska-Wasek W , Durlanik S , Garnett JP , Pflanz S . Polarized cytokine release from airway epithelium differentially influences macrophage phenotype. Mol Immunol. 2021; 132: 142- 149.

[48] Skronska-Wasek W , Durlanik S , Le HQ , et al. The antimicrobial peptide S100A8/A9 produced by airway epithelium functions as a potent and direct regulator of macrophage phenotype and function. Eur Respir J. 2022; 59 (4): 2002732.

[49] Morris CR , Habibovic A , Dustin CM , et al. Macrophage-intrinsic DUOX1 contributes to type 2 inflammation and mucus metaplasia during allergic airway disease. Mucosal Immunol. 2022; 15 (5): 977- 989.

[50] Choi JP , Park SY , Moon KA , et al. Macrophage-derived progranulin promotes allergen-induced airway inflammation. Allergy. 2020; 75 (5): 1133- 1145.

[51] Chen J , Chen S , Gong G , Yang F , Wang Y . Inhibition of IL-4/STAT6/IRF4 signaling reduces the epithelial-mesenchymal transition in eosinophilic chronic rhinosinusitis with nasal polyps. Int Immunopharmacol. 2023; 121: 110554.

[52] Takabayashi T , Kato A , Peters AT , et al. Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2013; 132 (3): 584- 592.e4.

[53] Shi LL , Ma J , Deng YK , et al. Cold-inducible RNA-binding protein contributes to tissue remodeling in chronic rhinosinusitis with nasal polyps. Allergy. 2021; 76 (2): 497- 509.

[54] Engler AE , Ysasi AB , Pihl RMF , et al. Airway-Associated macrophages in homeostasis and repair. Cell Rep. 2020; 33 (13): 108553.

[55] Han M , Breckenridge HA , Kuo S , et al. M2 Macrophages promote IL-33 expression, ILC2 expansion and mucous metaplasia in response to early life rhinovirus infections. Front Immunol. 2022; 13: 952509.

[56] Jenkins SJ , Ruckerl D , Cook PC , et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011; 332 (6035): 1284- 1288.

[57] Lee SH , Kang B , Kamenyeva O , et al. Dermis resident macrophages orchestrate localized ILC2 eosinophil circuitries to promote nonhealing cutaneous leishmaniasis. Nat Commun. 2023; 14 (1): 7852.

[58] Xiong G , Xie X , Wang Q , et al. Immune cell infiltration and related core genes expression characteristics in eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps. Exp Ther Med. 2020; 20 (6): 180.

[59] Kawasaki T , Ikegawa M , Yunoki K , et al. Alveolar macrophages instruct CD8(+) T cell expansion by antigen cross-presentation in lung. Cell Rep. 2022; 41 (11): 111828.

[60] Fu Y , Wang J , Zhou B , et al. An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment. Sci Immunol. 2022; 7 (68): eabi9768.

[61] Yao Y , Jeyanathan M , Haddadi S , et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell. 2018; 175 (6): 1634- 1650.e17.

[62] Chen PC , Shao YT , Hsieh MH , et al. Early-life EV-A71 infection augments allergen-induced airway inflammation in asthma through trained macrophage immunity. Cell Mol Immunol. 2021; 18 (2): 472- 483.

[63] Branchett WJ , Cook J , Oliver RA , et al. Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early-life allergen exposure. J Allergy Clin Immunol. 2021; 147 (5): 1892- 1906.

[64] Liu Y , Yuan Q , Zhang X , et al. Fine particulate matter (PM2.5) induces inhibitory memory alveolar macrophages through the AhR/IL-33 pathway. Cell Immunol. 2023; 386: 104694.

[65] Zahalka S , Starkl P , Watzenboeck ML , et al. Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling. Mucosal Immunol. 2022; 15 (5): 896- 907.

[66] Svedberg FR , Brown SL , Krauss MZ , et al. The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation. Nat Immunol. 2019; 20 (5): 571- 580.

[67] Hou Y , Wei D , Zhang Z , et al. FABP5 controls macrophage alternative activation and allergic asthma by selectively programming long-chain unsaturated fatty acid metabolism. Cell Rep. 2022; 41 (7): 111668.

[68] Yao A , Wilson JA , Ball SL . Autonomic nervous system dysfunction and sinonasal symptoms. Allergy Rhinol (Providence). 2018; 9: 2152656718764233.

[69] Sato E , Koyama S , Okubo Y , Kubo K , Sekiguchi M . Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol. 1998; 274 (6): L970- L979.

[70] Lim JE , Chung E , Son Y . A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNγ. Sci Rep. 2017; 7 (1): 9417.

[71] Chen M , Reed RR , Lane AP . Chronic inflammation directs an olfactory stem cell functional switch from neuroregeneration to immune defense. Cell Stem Cell. 2019; 25 (4): 501- 513.e5.

[72] Wellford SA , Chen CW , Vukovic M , et al. Distinct olfactory mucosal macrophage populations mediate neuronal maintenance and pathogen defense. Mucosal Immunol. 2024; 17 (5): 1102- 1113.

[73] Iwasaki N , Terawaki S , Shimizu K , et al. Th2 cells and macrophages cooperatively induce allergic inflammation through histamine signaling. PLoS One. 2021; 16 (3): e0248158.

RIGHTS & PERMISSIONS

The Author(s). Eye & ENT Research published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.