Nociceptor Neurons Are Involved in the Host Response to Urinary Tract Infections

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2022 Jun 15

PMID 35702548

Authors

Zhengdong Gao

Yaxiao Liu

Lekai Zhang

Zizhuo Yang

LinChen Lv

Shuai Wang

Lipeng Chen

Nan Zhou

Yaofeng Zhu

Xuewen Jiang

BenKang Shi

Yan Li

Affiliations

Soon will be listed here.

Abstract

Purpose: Urinary tract infections (UTIs) can evoke a rapid host immune response leading to bladder inflammation and epithelial damage. Neuroimmune interactions are critical for regulating immune function in mucosal tissues. Yet the role of nociceptor neurons in bladder host defense has not been well defined. This study aimed to explore the interaction between nociceptor neurons and bladder immune system during UTIs.

Methods: In this study, whether uropathogenic (UPEC) and lipopolysaccharide (LPS) can directly stimulate nociceptor neurons was detected. Female C57BL/6J mice were treated with high dose of capsaicin, a high-affinity TRPV1 agonist, to ablate nociceptor neurons. Bladder inflammation, barrier epithelial function and bladder immune cell infiltration were assessed after UPEC infection. The level of neuropeptide calcitonin gene-related peptide (CGRP) in infected bladder was detected. Furthermore, the effects of CGRP on neutrophils and macrophages were evaluated both in vitro and in vivo.

Results: We found that UPEC and its pathogenic factor LPS could directly excite nociceptor neurons, releasing CGRP into infected bladder, which suppressed the recruitment of neutrophils, the polarization of macrophages and the killing function of UPEC. Both Botulinum neurotoxin A (BoNT/A) and BIBN4096 (CGRP antagonism) blocked neuronal inhibition and prevented against UPEC infection.

Conclusion: The present study showed a novel mechanism by which UPEC stimulated the secretion of CGRP from nociceptor neurons to suppress innate immunity.

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References

Kolaczkowska E, Kubes P . Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013; 13(3):159-75. DOI: 10.1038/nri3399. View

Rohde K, Yates R, Purdy G, Russell D . Mycobacterium tuberculosis and the environment within the phagosome. Immunol Rev. 2007; 219:37-54. DOI: 10.1111/j.1600-065X.2007.00547.x. View

Gabanyi I, Muller P, Feighery L, Oliveira T, Costa-Pinto F, Mucida D . Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages. Cell. 2016; 164(3):378-91. PMC: 4733406. DOI: 10.1016/j.cell.2015.12.023. View

Hozzari A, Behzadi P, Kerishchi Khiabani P, Sholeh M, Sabokroo N . Clinical cases, drug resistance, and virulence genes profiling in Uropathogenic Escherichia coli. J Appl Genet. 2020; 61(2):265-273. DOI: 10.1007/s13353-020-00542-y. View

Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, Meyer-Schwesinger C . Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell. 2014; 156(3):456-68. PMC: 4258064. DOI: 10.1016/j.cell.2014.01.006. View

Veiga-Fernandes H, Artis D . Neuronal-immune system cross-talk in homeostasis. Science. 2018; 359(6383):1465-1466. DOI: 10.1126/science.aap9598. View

Baral P, Umans B, Li L, Wallrapp A, Bist M, Kirschbaum T . Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat Med. 2018; 24(4):417-426. PMC: 6263165. DOI: 10.1038/nm.4501. View

Grando S, Zachary C . The non-neuronal and nonmuscular effects of botulinum toxin: an opportunity for a deadly molecule to treat disease in the skin and beyond. Br J Dermatol. 2017; 178(5):1011-1019. DOI: 10.1111/bjd.16080. View

Buckley C, Gilroy D, Serhan C, Stockinger B, Tak P . The resolution of inflammation. Nat Rev Immunol. 2012; 13(1):59-66. DOI: 10.1038/nri3362. View

10.

Leng W, Chancellor M . How sacral nerve stimulation neuromodulation works. Urol Clin North Am. 2005; 32(1):11-8. DOI: 10.1016/j.ucl.2004.09.004. View

11.

Chermansky C, Chancellor M . Use of Botulinum Toxin in Urologic Diseases. Urology. 2016; 91:21-32. DOI: 10.1016/j.urology.2015.12.049. View

12.

Abraham S, Miao Y . The nature of immune responses to urinary tract infections. Nat Rev Immunol. 2015; 15(10):655-63. PMC: 4926313. DOI: 10.1038/nri3887. View

13.

Soehnlein O, Lindbom L . Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol. 2010; 10(6):427-39. DOI: 10.1038/nri2779. View

14.

Wu J, Miao Y, Abraham S . The multiple antibacterial activities of the bladder epithelium. Ann Transl Med. 2017; 5(2):35. PMC: 5300852. DOI: 10.21037/atm.2016.12.71. View

15.

Dale D, Boxer L, Liles W . The phagocytes: neutrophils and monocytes. Blood. 2008; 112(4):935-45. DOI: 10.1182/blood-2007-12-077917. View

16.

Shi X, Wang L, Clark J, Kingery W . Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways. Regul Pept. 2013; 186:92-103. PMC: 3799830. DOI: 10.1016/j.regpep.2013.08.001. View

17.

Kantari C, Pederzoli-Ribeil M, Witko-Sarsat V . The role of neutrophils and monocytes in innate immunity. Contrib Microbiol. 2008; 15:118-146. DOI: 10.1159/000136335. View

18.

Giannantoni A, Mearini E, Del Zingaro M, Proietti S, Porena M . Two-year efficacy and safety of botulinum a toxin intravesical injections in patients affected by refractory painful bladder syndrome. Curr Drug Deliv. 2009; 7(1):1-4. DOI: 10.2174/156720110790396463. View

19.

Brain S, Williams T . Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. Br J Pharmacol. 1985; 86(4):855-60. PMC: 1916626. DOI: 10.1111/j.1476-5381.1985.tb11107.x. View

20.

Russell D, Huang L, VanderVen B . Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol. 2019; 19(5):291-304. PMC: 7032560. DOI: 10.1038/s41577-019-0124-9. View